Para-amino benzoic acids as integrin antagonists

ABSTRACT

The present invention relates to compounds of the general formula (I), their preparation and use as pharmaceutical compositions asintegrin antagonists, especially as α 4 β and/or α 4 β   7 ?and/or α 9 β 1  intergrin antagonists and in particular for the production of pharmaceutical compositions suitable for the inhibition or the prevention of cell adhesion and cell-adhesion mediated disorders. Examples are the treatment and the prophylaxis of atherosclerosis, asthma, chronic obstructive pulmonary disease (COPD), allergies, diabetes, inflammatory bowel disease, multiple sclerosis, myocardial ischemia, rheumatoid arthritis, transplant rejection and other inflammatory, autoimmune and immune disorders.

The present invention relates to compounds of formula (I),

their preparation and use as pharmaceutical compositions as integrinantagonists, especially as α₄β₁ and/or α₄β₇ and/or aged integrinantagonists and in particular for the production of pharmaceuticalcompositions suitable for the inhibition or the prevention of celladhesion and cell-adhesion mediated disorders. Examples are thetreatment and the prophylaxis of atherosclerosis, asthma, chronicobstructive pulmonary disease (COPD), allergies, diabetes, inflammatorybowel disease, multiple sclerosis, myocardial ischemia, rheumatoidarthritis, transplant rejection and other inflammatory, autoimmune andimmune disorders.

Adhesive interactions between the leukocytes and endothelial cells playa critical role in leukocyte trafficking to sites of inflammation. Theseevents are essential for normal host defense against pathogens andrepair of tissue damage, but can also contribute to the pathology of avariety of inflammatory and autoimmune disorders. Indeed, eosinophil andT cell infiltration into the tissue is known as a cardinal feature ofallergic inflammation such as asthma.

The interaction of circulating leukocytes with adhesion molecules on theluminal surface of blood vessels appears to modulate leukocytetransmigration. These vascular cell adhesion molecules arrestcirculating leukocytes, thereby serving as the first step in theirrecruitment to infected or inflamed tissue sites. Subsequently, theleukocytes reaching the extravascular space interact with connectivetissue cells such as fibroblasts as well as extracellular matrixproteins such as fibronectin, laminin, and collagen. Adhesion moleculeson the leukocytes and on the vascular endothelium are hence essential toleukocyte migration and attractive therapeutic targets for interventionin many inflammatory disorders.

Leukocyte recruitment to sites of inflammation occurs in a stepwisefashion beginning with leukocyte tethering to the endothelial cellslining the blood vessels. This is followed by leukocyte rolling,activation, firm adhesion, and transmigration. A number of cell adhesionmolecules involved in those four recruitment steps have been identifiedand characterized to date. Among them, the interaction between vascularcell adhesion molecule 1 (VCAM-1) and very late antigen 4 (VLA-4, α₄β₁integrin), as well as the interaction between mucosal addressin celladhesion molecule 1 (MAdCAM-1) and α₄β₇ integrin, has been shown tomediate the tethering, rolling, and adhesion of lymphocytes andeosinophils, but not neutrophils, to endothelial cells under aphysiologic flow condition. This suggests that the VCAM-1/VLA-4 and/orMAdCAM-1/α₄β₇ integrin mediated interactions could predominantly mediatea selective recruitment of leukocyte subpopulations in vivo. Theinhibition of this interaction is a point of departure for therapeuticintervention (A. J. Wardlaw, J Allergy Clin. Immunol. 1999, 104,917-26).

VCAM-1 is a member of immunoglobulin (Ig) superfamily and is one of thekey regulators of leukocyte trafficking to sites of inflammation.VCAM-1, along with intracellular adhesion molecule 1 (ICAM-1) andE-selectin, is expressed on inflamed endothelium activated by suchcytokines as interleukin 1 (IL-1) and tumor necrosis factor a (TNF-α),as well as by lipopolysaccharide (LPS), via nuclear factor κB (NF-κB)dependent pathway. However, these molecules are not expressed on restingendothelium. Cell adhesion mediated by VCAM-1 may be involved innumerous physiological and pathological processes including myogenesis,hematopoiesis, inflammatory reactions, and the development of autoimmunedisorders. Integrins VLA-4 and α₄β₇ both function as leukocyte receptorsfor VCAM-1.

The integrin α₄β₁ is a heterodimeric protein expressed in substantiallevels on all circulating leukocytes except mature neutrophils. Itregulates cell migration into tissues during inflammatory responses andnormal lymphocyte trafficking. VLA-4 binds to different primary sequencedeterminants, such as a QIDSP motif of VCAM-1 and an ILDVP sequence ofthe major cell type-specific adhesion site of the alternatively splicedtype III connecting segment domain (CS-1) of fibronectin.

In vivo studies with neutralizing monoclonal antibodies and inhibitorpeptides have demonstrated a critical role for (%4 integrins interactionin leukocyte-mediated inflammation. Blocking of VLA-4/ligandinteractions, thus, holds promise for therapeutic intervention in avariety of inflammatory, autoimmune and immune diseases (Zimmerman, C.;Exp. Opin. Ther. Patents 1999, 9, 129-133).

Furthermore, compounds containing a bisarylurea moiety as a substituentwere disclosed as α₄β₁ integrin receptor antagonists: WO 96/22966, WO97/03094, WO 99/33789, WO 99/37605. However, no aminobenzoic acids oraminocycloalkylcarboxylic acids or homologues thereof or heterocyclicsanalogues thereof with α₄β₁ integrin receptor antagonists activity havebeen described.

3-[[[(phenylacetyl)amino]acetyl]amino]-benzoic acid has been describedin Bio-chemistry, Vol. 26, No. 12, 1987, 3385 as a substrate forβ-lactamases. N-(4-amino-phenylacetylglycyl)-4-aminophenylacetic acidhas been described in J. für prakt. Chem., 4. Reihe, Band 27, 1965, 63without giving a pharmaceutical use.N¹-[4-(eth-oxycarbonyl)phenyl]-N²-phenylacetyl)-α-glutamine andN²-benzoyl-N¹-[4-(ethoxy-carbonyl)phenyl]-α-glutamine and relatedcompounds have been described in Minerva Medica, 58 (86), 1967, 3651 andNL 6510006 as antisecretory agents.(S)-4-[[4-carboxy-1-oxo-2-[(phenylacetyl)amino]butyl]amino]-benzeneaceticacid has been described in Drugs Exp. Clin. Res. Suppl. 1, XII, 1987, 57as antitumor agent.N-[2-[[4-aminosulfonyl)phenyl]amino]-2-oxoethyl]-N-ethylbenzeneacetamidehas been described in Eur. J. Med. Chem.-Chim. Ther. 12 (4), 1977, 387with schistosomicide activity.N-(2-phenylacetylamino-acetylamino)-benzoic acid ethyl ester has beendescribed in Yakugaku Zasshi 79, 1959, 1606 in decomposition studies ofpenicillins. Japanese publication Hei 11-269135 describes3-aminosubstituted benzoic acid derivatives as selectin inhibitors.

None of these compounds have been described in relation to theinhibition or the prevention of cell adhesion and cell-adhesion mediateddisorders.

Further to their α₄β₁ integrin antagonistic activity, the compounds ofthe present invention may also be used as α₄β₇ or α₉β₁ integrinantagonists.

An object of the present invention is to provide new, alternative,aminobenzoic acids or aminocycloalkylcarboxylic acids or homologuesthereof or heterocyclic analogues thereof derived integrin antagonistsfor the treatment of inflammatory, autoimmune and immune diseases.

The present invention therefore relates to compounds of the generalformula (I):

-   -   wherein    -   R¹ represents hydrogen, C₁-C₄-alkyl, trifluormethyl,        trifluormethoxy, phenyl, —OR¹⁻², —SR¹⁻², NR¹⁻³R¹⁻⁴, —C(O)R¹⁻²,        S(O)R¹⁻², —SO₂R¹⁻², —CO₂R¹⁻², —OC(O)R¹⁻², —C(O)NR¹⁻³R¹⁻⁴,        —NR¹⁻²C(O)R¹⁻², —SO₂NR¹⁻³R¹⁻⁴, —NR¹⁻²SO₂R¹⁻²,        —NR₁₋₂C(O)NR¹⁻³R¹⁻⁴-NR¹⁻²C(O)OR¹⁻⁴, —OC(O)NR¹⁻³R¹⁻⁴, halogen,        cyano, nitro or amino,    -   wherein R¹⁻² represents hydrogen or C₁-C₄-alkyl,    -   wherein R¹⁻³ represents hydrogen or C₁-C₄-alkyl,    -   R¹⁻⁴ represents hydrogen, C₁-C₄-alkyl, C₃-C₆-cycloalkyl, C₆- or        C₁₀-aryl, heteroaryl or a heterocycle,    -   wherein R¹⁻⁴ can optionally be substituted by 1 to 2        substituents selected from the group C₁-C₄-alkyl, phenyl,        C₃-C₇-cycloalkyl, C₁-C₄-alkyloxy, halogen, nitro, cyano,    -   R² represents hydrogen or halogen, or    -   R¹ and R² together form a 4-7-membered ring, which includes the        carbon atoms to which R¹ and R² are bonded and which contains up        to 2 additional heteroatoms selected from the group oxygen,        nitrogen or sulfur and which contains up to 2 double bonds,        -   wherein the ring formed by R¹ and R² can optionally be            substituted by —NH—C₆— or C₁₀-aryl, —NH-heterocyclyl or            —NH-heteroaryl,        -   wherein C₆- or C₁₀-aryl can optionally be substituted by 1            to 2 substituents halogen, C₁-C₄-alkyl or C₁-C₄-alkoxy,    -   R³ represents hydrogen, C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl,        C₂-C₁₀-alkynyl, —(CH₂)_(m)—C₆— or C₁₀-aryl,        —(CH₂)_(m)—C₃-C₇-cycloalkyl, —(CH₂)_(m)-heterocyclyl or        —(CH₂)_(m)-heteroaryl,    -   wherein m represents an integer of zero to six,    -   wherein R³ can optionally be substituted by 1 to 3 radicals        R³⁻¹,    -   wherein R³⁻¹ represents trifluormethyl, trifluormethoxy, —OR³⁻²,        —NR³⁻³R³⁻⁴, —C(O)R³⁻², halogen, cyano, nitro, oxo, C₆- or        C₁₀-aryl, heterocyclyl, hetero-aryl,    -   wherein R³⁻² represents hydrogen, C₁-C₄-alkyl, C₃-C₆cycloalkyl,        C₆- or C₁₀-aryl,    -   and wherein R³⁻³ and R³⁻⁴ are identical or different and        represent hydrogen or C₁-C₄-alkyl,    -   R⁴ represents hydrogen, halogen, C₁-C₄-alkyl, C₁-C₄-alkoxy,        cyano, amino or nitro,    -   R⁵ represents hydrogen, C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl,        C₂-C₁₀-alkynyl, —(CH₂)_(n)—C₆— or C₁₀-aryl,        —(CH₂)_(n)—C₃-C₇-cycloalkyl, —(CH₂)_(n)-heterocyclyl,        —(CH₂)_(n)-heteroaryl,    -   wherein n represents an integer of zero to six,    -   wherein R⁵ can optionally be substituted by 1 to 3 radicals        R⁵⁻¹,    -   wherein R⁵⁻¹ represents C₁-C₄ alkyl, trifluormethyl,        trifluormethoxy, —OR⁵⁻², —NR⁵⁻³R⁵⁻⁴, —C(O)R⁵⁻², halogen, cyano,        nitro, oxo, C₆- or C₁₀-aryl, heterocyclyl, heteroaryl,    -   wherein R⁵⁻² represents hydrogen, C₁-C₄-alkyl, C₃-C₆-cycloalkyl,        C₆- or C₁₀-aryl or halogenated C₆- or C₁₀-aryl,    -   and wherein R⁵⁻³ and R⁵⁻⁴ are identical or different and        represent hydrogen or C₁-C₄-alkyl, or    -   R³ and R⁵ together form a 4-7-membered heterocyclic ring, which        includes the nitrogen atom to which R⁵ is bonded and the carbon        atom to which R³ is bonded and which contains up to 2 additional        heteroatoms selected from the group oxygen, nitrogen or sulfur        and which contains up to 2 double bonds,    -   R⁶ represents hydrogen, C₁-C₄ alkyl, —OR⁶⁻¹, —NR⁶⁻²R⁶⁻³,        —C(O)R⁶⁻¹, C₆-aryl, heterocyclyl, heteroaryl, halogen, cyano,        nitro, hydroxy, amino, trifluoromethyl, trifluoromethoxy,    -   wherein R⁶⁻¹ represents hydrogen, C₁-C₄-alkyl, C₃-C₆-cycloalkyl        or C₆-aryl,    -   wherein R⁶⁻² and R⁶⁻³ are identical or different and represent        hydrogen, C₁-C₄-alkyl, C₃-C₆-cycloalkyl or C₆-aryl,    -   and wherein R⁶, R⁶⁻¹, R⁶⁻² and R⁶⁻³ can optionally be        substituted by 1 to 2 radicals R⁶⁻⁴,    -   wherein R⁶⁻⁴ represents trifluoromethyl, trifluoromethoxy,        halogen, cyano, nitro, hydroxy, amino and oxo    -   R⁷ represents hydrogen or C₁-C₄ alkyl,    -   or R⁷ and R³ together with the carbon atoms to which they are        bonded form a cycloalkyl ring,    -   X represents oxygen or two hydrogen atoms,    -   and pharmaceutically acceptable salts thereof.

In the context of the present invention alkyl stands for astraight-chain or branched alkyl residue, such as methyl, ethyl,n-propyl, iso-propyl, n-pentyl. If not stated otherwise, preferred isC₁-C₁₀-alkyl, very preferred is C₁-C₆-alkyl, especially C₁-C₄-alkyl.

Alkenyl and alkynyl stand for straight-chain or branched residuescontaining one or more double or triple bonds, e.g. vinyl, allyl,isopropinyl, ethinyl. If not stated otherwise, preferred is C₁-C₁₀alkenyl or alkinyl, very preferred is C₁-C₆ alkenyl or alkinyl.

Cycloalkyl stands for a cyclic alkyl group such as cyclopropyl,cyclobutyl, cyclo-pentyl, cyclohexyl or cycloheptyl. Preferred isC₃-C₇-cycloalkyl, especially C₅-C₆-cycloalkyl.

—(CH₂)_(m)— or —(CH₂)_(n)— represent alkandiyl chains of the length m orn. —(CH₂)_(n)—C₆— or C₁₀-aryl, —(CH₂)_(n)—C₃-C₇-cycloalkyl,—(CH₂)_(n)-heterocyclyl, —(CH₂)_(n)-heteroaryl represent the respectiverings, which are bonded via the alkandiyl chain.

Halogen in the context of the present invention stands for fluorine,chlorine, bromine or iodine. If not specified otherwise, chlorine orfluorine are preferred. Halogenated stands for a substitution with 1 or2 fluorine or chlorine atoms.

Heteroaryl stands for a monocyclic heteroaromatic system containing 4 to9, especially 5 or 6 ring atoms, which contains 1, 2 or 3 heteroatomsindependently selected from the group consisting of nitrogen, oxygen andsulfur, and which can be attached via a carbon atom or eventually via anitrogen atom within the ring, for example, furan-2-yl, furan-3-yl,pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, thienyl, thiazolyl, oxazolyl,imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl or pyridazinyl.C₄-C₉ heteroaryl also stands for a 4 to 9-membered ring, wherein one ormore of the carbon atoms are replaced by heteroatoms. If not specifiedotherwise, pyridyl or thienyl are preferred.

A saturated or unsaturated heterocyclic residue (heterocycle) stands fora mono-cyclic system containing 4 to 9, especially 5 or 6 ring atoms,which contains 1, 2 or 3 heteroatoms independently selected from thegroup consisting of nitrogen, oxygen and sulfur, and which can containone or more double bonds and which can be attached via a ring carbonatom or eventually via a nitrogen atom, e.g. tetrahydrofur-2-yl,pyrrolidine-1-yl, piperidine-1-yl, piperidine-2-yl, piperidine-3-yl,piperidine-4-yl, piperazine-1-yl, piperazine-2-yl morpholine-1-yl,1,4-diazepine-1-yl or 1,4-dihydropyridine-1-yl.

If not specified otherwise, in the context of the present inventionheteroatom stands preferably for O, S, N or P.

Surprisingly, the compounds of the present invention show good integrinantagonistic activity. They are therefore suitable especially as α₄β₁and/or α₄α₇ and/or α₉β₁ integrin antagonists and in particular for theproduction of pharmaceutical compositions for the inhibition or theprevention of cell adhesion and cell-adhesion mediated disorders.Examples are the treatment and the prophylaxis of atherosclerosis,asthma, chronic obstructive pulmonary disease (COPD), allergies,diabetes, inflammatory bowel disease, multiple sclerosis, myocardialischemia, rheumatoid arthritis, transplant rejection and otherinflammatory, autoimmune and immune disorders.

The integrin antagonists of the invention are useful not only fortreatment of the physiological conditions discussed above, but are alsouseful in such activities as purification of integrins and testing foractivity.

In a preferred embodiment, the present invention relates to compounds ofgeneral formula (1),

-   -   wherein    -   R¹ represents —NR¹⁻²C(O)NR¹⁻³R¹⁻⁴,    -   wherein R¹⁻² represents hydrogen,    -   wherein R¹⁻³ represents hydrogen,    -   wherein R¹⁻⁴ represents C₆- or C₁₀-aryl or pyridyl,    -   wherein R¹⁻⁴ can optionally be substituted by 1 to 2        substituents C₁-C₄-alkyl, C₁-C₄-alkoxy or halogen,    -   R² represents hydrogen, halogen, C₁-C₄-alkyl or C₁-C₄-alkoxy, or    -   R¹ and R² together form a 4-6-membered heterocyclic or        heteroaromatic ring, which includes the carbon atoms to which R¹        and R² are bonded and which contains 1 or 2 additional        heteroatoms selected from the group oxygen and nitrogen and        which contains 1 or 2 double bonds,        -   wherein the ring formed by R¹ and R² can optionally be            substituted by —NH—C₆— or C₁₀-aryl,        -   wherein C₆— or C₁₀-aryl can optionally be substituted by 1            to 2 substituents halogen, C₁-C₄-alkyl or C₁-C₄-alkoxy,    -   R³ represents hydrogen, C₁-C₁₀-alkyl, —(CH₂)_(m)—C₆- or        C₁₀-aryl, —(CH₂)_(m)-C₃-C₇-cycloalkyl, —(CH₂)_(m)-heterocyclyl,        —(CH₂)m-heteroaryl,    -   wherein m represents an integer of one to four,    -   wherein R³ can optionally be substituted by 1 to 2 radicals        R³⁻¹,    -   wherein R³⁻¹ represents —OR³⁻², —NR³⁻³R³⁻⁴, —C(O)R³⁻², halogen,        cyano, nitro, oxo, C₆- or C₁₀-aryl, heterocyclyl, heteroaryl,    -   wherein R³⁻² represents hydrogen or C₁-C₄-alkyl,    -   and wherein R³⁻³ and R³⁻⁴ are identical or different and        represent hydrogen or C₁-C₄-alkyl,    -   R⁴ represents hydrogen, halogen, C₁-C₄-alkyl or C₁-C₄-alkoxy,    -   R⁵ represents hydrogen, C₁-C₁₀-alkyl, —(CH₂)_(n)—C₆— or        C₁₀-aryl, —(CH₂)_(n)—C₃-C₇-cycloalkyl, —(CH₂)_(n)-heterocyclyl,        —(CH₂)_(n)-heteroaryl,    -   wherein n represents an integer of one to three,    -   wherein R⁵ can optionally be substituted by 1 to 2 radicals        R⁵⁻¹,    -   wherein R⁵⁻¹ represents C₁-C₄-alkyl, —OR⁵⁻², —NR⁵⁻³R⁵⁻⁴,        —C(O)R⁵⁻², halogen, cyano, nitro, oxo, C₆- or C₁₀-aryl,        heterocyclyl, heteroaryl,    -   wherein R⁵⁻² represents hydrogen or C₁-C₄-alkyl,    -   and wherein R⁵⁻³ and R⁵⁻⁴ are identical or different and        represent hydrogen or C₁-C₄-alkyl,    -   R⁶ represents hydrogen,    -   R⁷ represents hydrogen or C₁C₄ alkyl,    -   or R⁷ and R³ together with the carbon atoms to which they are        bonded form a cycloalkyl ring,    -   X represents oxygen or two hydrogen atoms,    -   and pharmaceutically acceptable salts thereof.

In another preferred embodiment, the present invention relates tocompounds of general formula (I),

-   -   wherein    -   R¹ represents —NR¹⁻²C(O)NR¹⁻³R¹⁻⁴,    -   wherein R¹⁻² represents hydrogen,    -   wherein R¹⁻³ represents hydrogen,    -   wherein R¹⁻⁴ represents C₆-aryl,    -   wherein R¹⁻⁴ is substituted by 1 to 2 substituents C₁-C₄-alkyl,    -   R² represents hydrogen, or    -   R¹ and R² together form a 5-membered heterocyclic or        heteroaromatic ring, which includes the carbon atoms to which R¹        and R² are bonded and which contains 1 or 2 additional        heteroatoms selected from the group oxygen and nitrogen and        which contains 1 or 2 double bonds,        -   wherein the ring formed by R¹ and R² can optionally be            substituted by —NH—C₆ aryl,        -   wherein C₆— or C₁₀-aryl can optionally be substituted by 1            to 2 substituents halogen, C₁-C₄-alkyl or C₁-C₄-alkoxy,    -   R³ represents hydrogen, C₁-C₁₀-alkyl, —(CH₂)_(m)—C₆-aryl,        —(CH₂)_(m)—C₃-C₇-cycloalkyl, —(CH₂)_(m)-heterocyclyl,        —(CH₂)_(m)-heteroaryl,    -   wherein m represents an integer of one or two,    -   wherein R³ can optionally be substituted by 1 to 2 radicals        R³⁻¹,    -   wherein R³⁻¹ represents —OR³⁻², NR³⁻³R³⁻⁴, —C(O)R³⁻², halogen,        oxo, C₆— or C₁₀-aryl, heterocyclyl, heteroaryl,    -   wherein R³⁻² represents hydrogen or C₁-C₄-alkyl,    -   and wherein R³⁻³ and R³⁻⁴ are identical or different and        represent hydrogen or C₁-C₄-alkyl,    -   R⁴ represents hydrogen; halogen, C₁-C₄-alkyl or C₁-C₄-alkoxy,    -   R⁵ represents hydrogen, C₁-C₁₀-alkyl, —(CH₂), —C₆-aryl, —(CH₂),        —C₃-C₇-cycloalkyl, —(CH₂)_(n)-heterocyclyl,        —(CH₂)_(n)-heteroaryl,    -   wherein n represents an integer of one to three,    -   wherein R⁵ can optionally be substituted by 1 to 2 radicals        R⁵⁻¹,    -   wherein R⁵⁻¹ represents C₁-C₄-alkyl, —OR⁵⁻², —NR⁵⁻³R⁵⁻⁴,        —C(O)R⁵⁻², halogen, cyano, nitro, oxo, C₆- or C₁₀-aryl,        heterocyclyl, heteroaryl,    -   wherein R⁵⁻² represents hydrogen or C₁-C₄-alkyl,    -   and wherein R⁵⁻³ and R⁵⁻⁴ are identical or different and        represent hydrogen or C₁-C₄-alkyl,    -   R⁶ represents hydrogen,    -   R⁷ represents hydrogen,    -   X represents oxygen,    -   and pharmaceutically acceptable salts thereof.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), wherein R¹ represents a group of theformula

In another preferred embodiment, the present invention relates tocompounds of general formula (I), wherein the group of the formula

represents a group of the formula

In another preferred embodiment, the present invention relates tocompounds of general formula (I), wherein the group of the formula

represents a group of the formula

In another more preferred embodiment, the present invention relates tocompounds of general formula (I),

-   wherein R³ represents hydrogen.

In another more preferred embodiment, the present invention relates tocompounds of general formula (I),

-   wherein R⁶ represents hydrogen.

In another more preferred embodiment, the present invention relates tocompounds of general formula (I),

-   wherein R⁷ represents hydrogen.

In a very preferred embodiment, the present invention relates tocompounds of general formula (I), wherein the compound is selected fromthe following group:

-   4-[(N²-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-D-lysyl)amino]benzoic    acid trifluoroacetate,-   4-[(N-[3-(dimethylamino)propyl]-N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}glycyl)amino]benzoic    acid,-   4-[(N-(4-aminobutyl)-N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)-phenyl]acetyl}glycyl)amino]benzoic    acid,-   4-({N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-N-[3-(1-pyrrolidinyl)propyl]glycyl}amino)benzoic    acid,-   4-[(N-[(1-ethyl-2-pyrrolidinyl)methyl]-N-{[4-({[(2-methylphenyl)amino]-carbonyl}amino)phenyl]acetyl}glycyl)amino]benzoic    acid,-   4-({N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-N-[3-(4-phenyl-1-piperazinyl)propyl]glycyl}amino)benzoic    acid,-   4-{[N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-N-(tetrahydro-2-furanylmethyl)glycyl]amino}benzoic    acid,-   4-{[N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-N-(4-piperidinylmethyl)glycyl]amino}benzoic    acid,-   4-[(N-(3-amino-2,2-dimethylpropyl)-N-{[4-({[(2-methylphenyl)amino]-carbonyl}amino)phenyl]acetyl}glycyl)amino]benzoic    acid,-   4-({N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-N-[2-(1-pyrrolidinyl)ethyl]glycyl}amino)benzoic    acid,-   4-[(N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-N-propylglycyl)amino]benzoic    acid,-   4-({N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-N-[3-(2-oxo-1-pyrrolidinyl)propyl]glycyl}amino)benzoic    acid,-   4-[(N-(2-methoxyethyl)-N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)-phenyl]acetyl}glycyl)amino]benzoic    acid,-   4-({N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-N-[3-(4-morpholinyl)propyl]glycyl}amino)benzoic    acid,-   4-{[N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-N-(3-pyridinylmethyl)glycyl]amino}benzoic    acid,-   4-{[N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-N-(2-pyridinylmethyl)glycyl]amino}benzoic    acid,-   4-{[N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-N-(4-yridinylmethyl)glycyl]amino}benzoic    acid,-   4-[(N-[2-(1H-imidazol-4-yl)ethyl]-N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}glycyl)amino]benzoic    acid,-   4-({N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-N-[2-(2-pyridinyl)ethyl]glycyl}amino)benzoic    acid,-   4-({N-[(2-anilino-1,3-benzoxazol-6-yl)acetyl]glycyl}amino)benzoic    acid,-   4-{[N-[(2-anilino-1,3-benzoxazol-6-yl)acetyl]-N-(2-phenylethyl)glycyl]-amino}benzoic    acid,-   4-({N-[(2-anilino-1,3-benzoxazol-6-yl)acetyl]-N-[2-(2-pyridinyl)ethyl]glycyl}amino)benzoic    acid,-   4-({N-[(2-anilino-1,3-benzoxazol-6-yl)acetyl]-N-[2-(3,5-dimethoxyphenyl)-ethyl]glycyl}amino)benzoic    acid,-   4-{[N-({2-[(2-methylphenyl)amino]-1,3-benzoxazol-6-yl}acetyl)glycyl]-amino}benzoic    acid,-   4-{[N-({2-[(2-methylphenyl)amino]-1,3-benzoxazol-6-yl}acetyl)-N-(2-phenylethyl)glycyl]amino}benzoic    acid,-   4-({N-({2-[(2-methylphenyl)amino]-1,3-benzoxazol-6-yl}acetyl)-N-[2-(2-pyridinyl)ethyl]glycyl}amino)benzoic    acid,-   4-[(N-[2-(3-methoxyphenyl)ethyl]-N-{[4-({[(2-methylphenyl)amino]-carbonyl}amino)phenyl]acetyl}glycyl)amino]benzoic    acid,-   4-[(N-benzyl-N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]-acetyl}glycyl)amino]benzoic    acid,-   4-({N-[(2-anilino-1,3-benzoxazol-6-yl)acetyl]-N-[2-(3-methoxyphenyl)ethyl]-glycyl}amino)benzoic    acid,-   4-[(N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-L-phenylalanyl)amino]benzoic    acid,-   4-({N-[(2-anilino-1,3-benzoxazol-6-yl)acetyl]-L-phenylalanyl}amino)benzoic    acid,-   4-[(4-bromo-N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]-acetyl}-L-phenylalanyl)amino]benzoic    acid-   4-[(N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}glycyl)amino]benzoic    acid-   4-{[(2S)-4-amino-2-({[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}amino)butanoyl]amino}benzoic    acid-   4-[(N²-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-L-ornithyl)amino]benzoic    acid-   4-[(N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-L-α-aspartyl)amino]benzoic    acid-   4-[(N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-L-tryptophyl)amino]benzoic    acid-   4-{[N-{[4-(f{[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-3-(4-pyridinyl)-L-alanyl]amino}benzoic    acid-   4-{[N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-3-(3-pyridinyl)-L-alanyl]amino}benzoic    acid-   4-{[N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-3-(1,3-thiazol-4-yl)-L-alanyl]amino}benzoic    acid-   4-[(N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-L-histidyl)amino]benzoic    acid-   4-{[(1-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-2-piperazinyl)carbonyl]amino}benzoic    acid-   4-[3-({[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}amino)-1-piperidinyl]benzoic    acid-   4-[3-({[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}amino)-1-pyrrolidinyl]benzoic    acid-   4-[isobutyl(N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}glycyl)amino]benzoic    acid-   4-[isobutyl(N-(3-methoxypropyl)-V-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}glycyl)amino]benzoic    acid and-   4-[(N-(3-methoxypropyl)-N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}glycyl)(methyl)amino]benzoic    acid.

A preferred process for preparation of compounds of general formula (I)has also been found, which comprises reaction of carboxylic acids ofgeneral formula (V)

or activated derivatives thereof,

-   with compounds of the general formula (VI)    in the presence of a coupling agent and a base in inert solvents,    which will be described in more detail in the descriptive part of    the specification.

For the treatment of the above-mentioned diseases, the compoundsaccording to the invention can exhibit non-systemic or systemicactivity, wherein the latter is preferred. To obtain systemic activitythe active compounds can be administered, among other things, orally orparenterally, wherein oral administration is preferred.

For parenteral administration, forms of administration to the mucousmembranes (i.e. buccal, lingual, sublingual, rectal, nasal, pulmonary,conjunctival or intravaginal) or into the interior of the body areparticularly suitable. Administration can be carried out by avoidingabsorption (i.e. intracardiac, intra-arterial, intravenous, intraspinalor intralumbar administration) or by including absorption (i.e.intracutaneous, subcutaneous, percutaneous, intramuscular orintraperitoneal administration).

For the above purpose the active compounds can be administered per se orin administration forms.

Suitable administration forms for oral administration are, inter alia,normal and enteric-coated tablets, capsules, coated tablets, pills,granules, pellets, powders, solid and liquid aerosols, syrups,emulsions, suspensions and solutions. Suitable administration forms forparenteral administration are injection and infusion solutions.

The active compound can be present in the administration forms inconcentrations of from 0.001-100% by weight; preferably theconcentration of the active compound should be 0.5-90% by weight, i.e.quantities which are sufficient to allow the specified range of dosage.

The active compounds can be converted in the known manner into theabovementioned administration forms using inert non-toxicpharmaceutically suitable auxiliaries, such as for example excipients,solvents, vehicles, emulsifiers and/or dispersants.

The following auxiliaries can be mentioned as examples: water, solidexcipients such as ground natural or synthetic minerals (e.g. talcum orsilicates), sugar (e.g. lactose), non-toxic organic solvents such asparaffins, vegetable oils (e.g. sesame oil), alcohols (e.g. ethanol,glycerol), glycols (e.g. polyethylene glycol), emulsifying agents,dispersants (e.g. polyvinylpyrrolidone) and lubricants (e.g. magnesiumsulphate).

In the case of oral administration tablets can of course also containadditives such as sodium citrate as well as additives such as starch,gelatin and the like. Flavour enhancers or colorants can also be addedto aqueous preparations for oral administration.

For the obtainment of effective results in the case of parenteraladministration it has generally proven advantageous to administerquantities of about 0.001 to 100 mg/kg, preferably about 0.01 to 1 mg/kgof body weight. In the case of oral administration the quantity is about0.01 to 100 mg/kg, preferably about 0.1 to 10 mg/kg of body weight.

It may nevertheless be necessary to use quantities other than thosementioned above, depending on the body weight concerned, the method ofadministration, the individual response to the active compound, the typeof preparation and the time or interval of administration.

Suitable pharmaceutically acceptable salts of the compounds of thepresent invention that contain an acidic moiety include addition saltsformed with organic or inorganic bases. The salt forming ion derivedfrom such bases can be metal ions, e.g., aluminum, alkali metal ions,such as sodium of potassium, alkaline earth metal ions such as calciumor magnesium, or an amine salt ion, of which a number are known for thispurpose. Examples include ammonium salts, arylalkylamines such asdibenzylamine and N,N-dibenzylethylenediamine, lower alkylamines such asmethylamine, t-butylamine, procaine, lower alkylpiperidines such asN-ethylpiperidine, cycloalkyl-amines such as cyclohexylamine ordicyclohexylamine, 1-adamantylamine, benzathine, or salts derived fromamino acids like arginine, lysine or the like. The physiologicallyacceptable salts such as the sodium or potassium salts and the aminoacid salts can be used medicinally as described above and are preferred.

Suitable pharmaceutically acceptable salts of the compounds of thepresent invention that contain a basic moiety include addition saltsformed with organic or inorganic acids. The salt forming ion derivedfrom such acids can be halide ions or ions of natural or unnaturalcarboxylic or sulfonic acids, of which a number are known for thispurpose. Examples include chlorides, acetates, trifluoroacetates,tartrates, or salts derived from amino acids like glycine or the like.The physiologically acceptable salts such as the chloride salts, thetrifluoroacetic acid salts and the amino acid salts can be usedmedicinally as described below and are preferred.

These and other salts which are not necessarily physiologicallyacceptable are useful in isolating or purifying a product acceptable forthe purposes described below.

The salts are produced by reacting the acid form of the inventioncompound with an equivalent of the base supplying the desired basic ionor the basic form of the invention compound with an equivalent of theacid supplying the desired acid ion in a medium in which the saltprecipitates or in aqueous medium and then lyophilizing. The free acidor basic form of the invention compounds can be obtained from the saltby conventional neutralization techniques, e.g., with potassiumbisulfate, hydrochloric acid, sodium hydroxide, sodium bicarbonate, etc.

The compounds according to the invention can form non covalent additioncompounds such as adducts or inclusion compounds like hydrates orclathrates. This is known to the artisan and such compounds are alsoobject of the present invention.

The compounds according to the invention can exist in differentstereoisomeric forms, which relate to each other in an enantiomeric way(image and mirror image) or in a diastereomeric way (image differentfrom mirror image). The invention relates to the enantiomers and thediastereomers as well as their mixtures. They can be separated accordingto customary methods.

The compounds according to the invention can exist in tautomeric forms.This is known to the artisan and such compounds are also object of thepresent invention.

General Compound Synthesis

The synthesis of compounds according to the general formula (1) can beillustrated by the following scheme 1:

By coupling of the carboxylic acids or activated derivatives (II) withthe amines (III), followed by removal of the protecting group PG¹ theamides (V) can be obtained. Coupling with the carboxylic acids (VI)followed by removal of the protecting group PG² affords carboxylic acidsof type (VIII.

In the above scheme, AG stands for hydroxyl or a suitable activatinggroup forming an activated carboxylic acid derivative. Activatedcarboxylic acids derivatives of this type are known to the personskilled in the art and are described in detail in standard textbookssuch as, for example in (i) Houben-Weyl, Methoden der organischen Chemie[Methods of Organic Chemistry], Georg mhieme Verlag, Stuttgart or (ii)

Comprehensive Organic Synthesis, Ed. B. M. Trost, Pergamon Press,Oxford, 1991. The carboxylic acid is preferably activated as mixedanhydride, such as, for example, AG=iso-butyl-carbonate; asN-carboxyanhydride (R⁵ and AG=—CO—); or by a coupling agents such as,for example dicyclohexylcarbodiimid (DCC),1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide×HCl (EDCI),2-(7-aza-3-oxido-1H-1,2,3-benzo-triazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate. Other activated carboxylic acid derivatives suchas, for example symmetric anhydrides, halides, or activated esters e.g.succinyl or pentafluorophenyl esters may also be employed.

In the above scheme PG¹ stands for a suitable protecting group of theamino group that is stable under the respective reaction conditions.Protecting groups of this type are known to the person skilled in theart and are described in detail in T. W. Greene, P. G. Wuts, ProtectiveGroups in Organic Synthesis, 3^(rd) ed., John Wiley, New York, 1999. Theamino group is preferably protected by carbamates, PG¹ being for exampletert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (FMOC) orbenzyloxy-carbonyl (Cbz-/Z-) or other oxycarbonyl derivatives.

In the above scheme PG² stands for a suitable protecting group of thecarboxyl group or COOPG² stands for the carboxylic group attached to apolymeric resin suitable for solid phase synthesis. Protecting groups ofthis type are known to the person skilled in the art and are describedin detail in T. W. Greene, P. G. Wuts, Protective Groups in OrganicSynthesis, 3^(rd) ed., John Wiley, New York, 1999. The carboxyl group ispreferably esterified, PG² being C₁₋₆-alkyl such as, for example,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl,isopentyl, neopentyl, hexyl, a C₃₋₇-cycloalkyl such as, for example,cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclo-pentyl, cyclohexyl, anaryl such as, for example, phenyl, benzyl, tolyl or a substitutedderivative thereof.

Step A

Formation of the amides (IV) can take place by reacting an activatedform of the respective carboxylic acid (II), such as aN-carboxyanhydride or an iso-butylcarbonate with the desired amine (III)or an acceptable salt thereof

N-carboxyanhydrides of (II) are commercially available or can beprepared for example by the reaction of theBis-(N-tert-butyloxycarbonyl) protected derivative of (II) withthionylchloride and pyridine in dimethylformamide or by the reaction ofthe free amino acid of (II) with phosgene or with phosgene equivalentssuch as diphosgene, triphosgene or methylchloroformate.Iso-butylcarbonates can be prepared in situ by reaction of theN-protected amino acid (II) with iso-butylchloroformate as describedbelow. Activated derivatives of the acids (II) such as other anhydrides,halides, esters e.g. succinyl or pentafluorophenyl esters or activatedcarboxylic acids obtained by the reaction with coupling agents such as,for example dicyclohexyl-carbodiimid (DCC),1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide×HCl (EDCI),2-(7-aza-3-oxido-1H-1,2,3-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate may also be employed.

For example, amides of type (IV) can be prepared as follows:

1) N-carboxyanhydride Procedure

A solution/suspension of the amine (III), the N-carboxyanhydride of (II)and catalytic amounts of 4-(N,N′-dimethylamino)pyridine in an inertsolvent was refluxed for 0.5-14 days with exclusion of moisture. Theproduct was either isolated by filtration or by aqueous workup employingstandard procedures. If necessary the product was purified bytrituration or by flash-chromatography or used without furtherpurification.

2) Mixed Anhydride Procedure

A solution of the carboxylic acid derivative (II) and ofN-methylmorpholine in an inert solvent was cooled to −15° C. andiso-butyl chloroformate was added and stirred at 0° C. The amine (III)in an inert solvent was added at −15° C. The solution was stirred at 0°C., and at r.t. and was evaporated. The residue was redissolved in ethylacetate, washed with aqueous acid and base, dried and evaporated. Ifnecessary the product was purified by trituration or byflash-chromatography or used without further purification.

Compounds of general formula (II) are commercially available, known orcan be prepared by customary methods starting from known α-amino acidsor precursors for customary α-amino acid synthesis. For the preparationprocess according to the invention, the amino group is in this caseblocked by a conventional protective group PG¹.

In the α-position to the carboxyl group, these carboxylic acidderivatives can have substituents such as described under R³ and R⁴, forexample, hydrogen, a C₁-C₁₀-alkyl, a C₃-C₇-cycloalkyl, an aryl, analkenyl residue, or an alkinyl residue. The alkyl, alkenyl andcycloalkyl residues and the benzyl residue can be introduced by reactionof the ester of the starting compounds with the appropriate alkyl,alkenyl, cycloalkyl or benzyl halides in basic medium, if thecorresponding derivatives are not commercially available. The alkinylresidue can be introduced, for example, by reaction of the bromo esterof the present starting compound with an appropriate acetylide anion. Inthe case of the phenyl residue the starting materials used arepreferably the corresponding α-phenyl-α-aminocarboxylic acid derivativesand, if necessary, the other substituents at the α-C atom to theterminal carboxyl group are introduced via the appropriate alkyl halide.

The above reactions and their implementation are well known to theperson skilled in the art and are described in detail in standardtextbooks such as, for example, in (i) Houben-Weyl, Methoden derorganischen Chemie [Methods of Organic Chemistry], Georg Thieme Verlag,Stuttgart or Stuttgart or (ii) Comprehensive Organic Synthesis, Ed. B.M. Trost, Pergamon Press, Oxford, 1991.

If the substituents themselves should be substituted, e.g. by R′,appropriate reactive groups should be present in the substituent toallow further functionalization. These reactive groups should be inertto the reaction conditions of the previous step. For this purpose, thesubstituent can also be unsaturated to allow further functionalizationsuch as palladium catalyzed C—C-coupling reactions (e.g. Heck-reactionor Sonoga-shira-reaction), eventually followed by hydrogenation (scheme2):

In the abovementioned scheme PG⁴ stands for a protecting group of thecarboxyl group as described under PG², hal stands for a leaving groupsuch as a halogen, tosyl, mesyl or triflate, [Pd] stands for aPalladium(0) or Palladium(II) moiety. PG³ stands for a protecting groupof the amino group such as described under PG¹. Protecting groups ofthis type are known to the person skilled in the art and are describedin detail in T. W. Greene, P. G. Wuts, Protective Groups in OrganicSynthesis, 3^(rd) ed., John Wiley, New York, 1999.

If the substituent R³ in the α-position to the carboxylic group carry anappropriate substituted aryl or heteroaryl unit, another method forinsertion of an additional substituent are the C—C-coupling reactions asdescribed under the synthesis of precursors (VI).

Compounds of general formula (III) are commercially available, known orcan be prepared by customary methods starting from known carboxylic acidderivatives.

Step B

The removal of protecting group PG¹ can be performed, depending on thenature of PG¹, either by an acid such as trifluoroacetic acid (forexample in the case PG¹ is tert-butyloxycarbonyl (Boc)), a base such aspiperidine (for example in the case PG¹ is 9-fluorenylmethyloxycarbonyl(FMOC)) or by catalytic hydrogenation (for example in the case PG¹ isbenzyloxycarbonyl (Cbz-/Z-)).

Step C

Formation of the amides (VII) can take place by reacting the respectivecarboxylic acids (VI)— activated by a coupling agent such as DCC andHOBt; EDCI and HOBt or HATU—with the desired amines (V) or an acceptablesalt thereof. Activated derivatives of the acids (VI) such asanhydrides, halides, and esters e.g. succinyl or pentafluorophenylesters may also be employed.

For example, amides (VII) can be prepared as follows:

A solution of carboxylic acid, HOBt and EDCI in an inert solvent isstirred at r.t. After addition of the amine and a non-nucleophilic basesuch as ethylisopropylamine stirring is continued at r.t. or elevatedtemperature. The reaction mixture is poured into water and worked up bystandard procedures.

Compounds of general formula (VI) are commercially available, known orcan be prepared by customary methods starting from known carboxylic acidderivatives.

For example, biphenyl substituted acetic acid derivatives can beprepared by means of an aryl-aryl coupling of the respective phenylacetic acid derivatives and a suitable phenyl system.

Possible coupling reactions are, for example, the reaction of twounsubstituted phenyl groups in the presence of AlCl₃ and an acid (Schollreaction), the coupling of the two phenyl iodides in the presence ofcopper (Ullmann reaction), the reaction of the unsubstituted carboxylicacid derivative with a phenyldiazonium compound under basic conditions(Gomberg-Bachmann reaction) or coupling with participation oforganometallic reagents such as coupling of a phenyl halide with anorganometallic phenyl compound in the presence of a palladium compound,for example, a Pd(0), a Pd(II) or a Pd(IV) compound, and of a phosphanesuch as triphenylphosphane (e.g. Suzuki reaction).

Bisarylureas can be prepared by coupling of an amino phenyl acetic acidderivative and a phenylisocyanate. Bisarylamides can be prepared bycoupling of an amino phenyl acetic acid and an activated benzoic acidderivative such as described under Step A. Bisarylcarbamates can beprepared by coupling of an isocyanato phenyl acetic acid ester and aphenol derivative followed by saponification as described in Step D.

Anilinobenzoxazoles can be prepared by coupling of arylisothiocyanateswith ortho-amino-hydroxyphenyl derivatives and subsequent cyclization tothe corresponding anilino-benzoxazole derivatives in the presence ofsuitable desulfurization reagents, for example carbodiimides ormercury(II) salts.

Step D

The removal of the protecting group PG² can be performed either by anacid such as trifluoroacetic acid or an base such as potassium hydroxideor lithium hydroxide, depending on the nature of PG². Reactions arecarried out in aqueous, inert organic solvents such as alcohols e.g.methanol or ethanol, ethers e.g. tetrahydrofurane or dioxane or polaraprotic solvents e.g. dimethylformamide. If necessary, mixtures of theabove solvents may be used.

In case PG² stands for polymeric resin, the removal can take place usingstrong acid such as trifluoroacetic acid in dichloromethane.

EXAMPLES

Abbreviations AcOH acetic acid Boc tert-butyloxycarbonyl DCCdicyclohexylcarbodiimid GC gas chromatography DIPEAdiisopropylethylamine DMF dimethylformamide EDCI1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide × HCl eq. equivalents FCflash chromatography HATU 2-(7-aza-3-oxido-1H-1,2,3-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HOBtN-hydroxybenzotriazole monohydrate HPLC high performance liquidchromatography ICAM-1 intracellular adhesion molecule 1 IL-1 interleukin1 LPS lipopolysaccharide MAdCAM-1 mucosal addressin cell adhesionmolecule 1 MeOH methanol MeCN acetonitrile min. minutes M.p. meltingpoint NF-κB nuclear factor κB NMR nuclear magnetic resonance n.d. notdetermined r.t. room temperature R_(f) TLC: R_(f) value = distance spottraveled/ distance solvent front traveled TFA trifluoroacetic acid THFtetrahydrofurane TLC thin layer chromatography TNF-α tumor necrosisfactor α t_(R) retention time determined by HPLC VCAM-1 vascular celladhesion molecule 1 VLA-4 very late antigen 4 (α₄β₁ integrin)General remarks

In the examples below, all quantitative data, if not stated otherwise,relate to percentages by weight.

For synthetic process some compounds are immobilized on solid phase. Apreferred polymeric resin for this purpose is Wang polystyrene resin(Rapp-Polymere, Tüibingen). As known to the one skilled in the art, thecompounds can also be prepared by liquid synthetic methods usingessentially the same reagents. In this case Wang polystyrene resin issubstituted by an protection group for carboxyl groups such as esters.

Flash chromatography was carried out on silica gel 60, 40-63 μm (E.Merck, Darmstadt, Germany).

Thin layer chromatography was carried out, employing silica gel 60 F₂₅₄coated aluminum sheets (E. Merck, Darmstadt, Germany) with the mobilephase indicated.

Melting points were determined in open capillaries and are notcorrected.

All retention times are indicated in minutes and, if not statedotherwise, were determined by high-performance liquid chromatography(HPLC) by means of UV detection at 210 or 214/250 μm, at a flow rate of1 ml/min at ambient temperature with linear gradients. An MeCN/H₂Omixture with 0.1% TFA (vol./vol.) was used as eluent.

Method A:

Column: LiChrospher 100 RP-18, 5 μm, 250×4 mm (E. Merck, Darmstadt,Germany)

Gradient: 0 min MeCN/H₂O 0:100, 25 min MeCN/H₂O 100:0, 31 min MeCN/H₂O100:0, 32 min MeCN/H₂O 0:100, 38 min MeCN/H₂O 0:100.

Method B:

Column: Purospher RP-18, 5 μm, 250×4 mm (E. Merck, Darmstadt, Germany).

Gradient: 0 min MeCN/H₂O 0:100, 25 rmin MeCN/H₂O 100:0, 31 min MeCN/H₂O100:0, 32 min MeCN/H₂O 0:100, 38 min MeCN/H₂O 0:100.

Method C:

Column: Eurospher 100, C18, 5 μm, 120×4 mm (Knauer, Berlin,Deutschland).

Gradient: 0 min MeCN/H₂O 10:90, 13 min MeCN/H₂O 80:20, 15 min MeCN/H₂O80:20, 17 min MeCN/H₂O10:90.

Method D

Column: LiChrospher 100 RP-18, 5 μm, 250×4 mm (E. Merck, Darmstadt,Germany).

Gradient: 0 min MeCN/H₂O 10:90, 25 min MeCN/H₂O 100:0, 31 min MeCN/H₂O100:0, 32 min MeCN/H₂O 10:90, 38 min MeCN/H₂O 10:90.

The mass determinations were carried out using the electron sprayionization (ESI) method employing loop injection or split injection viaa HPLC system.

Precursor Synthesis

Example I 2-{4-[(2-Toluidinocarbonyl)amino]phenyl}acetic acid

To a solution of 2-(4-aminophenyl)acetic acid (108.8 g, 0.72 mol) inCH₂Cl₂ (1.0 l) and triethylamine (120 ml) was added a solution of2-methylphenyl isocyanate (90.5 ml, 0.72 mol) in CH₂Cl₂ (500 ml)dropwise at r.t. After stirring for 18 h at r.t., water (2.5 l) andCH₂Cl₂ (2.0 l) were added and the layers were separated. The organiclayer was extracted with water (3×400 ml). The combined aqueous layerswere concentrated to 3.0 l and acidified to pH 2 by the addition ofconcentrated aqueous HCl. The precipitate was collected by filtration,washed with cold water and dried in an exsiccator over concentratedH₂SO₄ affording 166.5 g (82%) white solid. M.p. 205-206° C.; TLC(CH₂Cl₂/MeOH 9:1): R_(f) 0.14. ¹H-NMR (400 MHz, D₆-DMSO): 12.21 (br s,1H), 9.11 (s, 1H), 8.00 (s, 1H), 7.83 (d, 7.6 Hz, 1H), 7.40 (d, 8.5 Hz,2H), 7.17-7.12 (m, 4H), 6.96-6.92 (m, 1H), 3.48 (s, 2H), 2.24 (s, 3H).

Example IV Methyl 4-({[(3-methoxypropyl)amino]acetyl}amino)benzoate

To a solution of methyl 4-aminobenzoate (10.0 g, 66.2 mmol) andtriethylamine (10.1 ml, 72.8 mmol) in dichloromethane (100 ml) was addeda solution of bromo-acetylbromide (6.34 ml, 72.8 mmol) indichloromethane (30 ml) at 0° C. After stirring for 18 h at roomtemperature and 18 h under reflux the reaction mixture was concentratedunder vacuum. The residue was taken up in ethyl acetate, washed with 1 Naqueous HCl and water, dried over MgSO₄ and evaporated. Yield 15.8 g(88%) of methyl 4-[(bromoacetyl)amino]benzoate as a pale brown solid.M.p.: 144-146° C., TLC (hexane/ethyl acetate 1:1): R_(f) 0.46; ¹H-NMR(400 MHz, D₆-DMSO) 10.77 (s, 1H), 7.95 (d, 8.7 Hz, 2), 7.73 (d, 8.7 Hz,2H), 4.08 (s, 2H), 3.83 (s, 3H); ESI-MS: [M+H⁺]=271.8

To a solution of methyl 4-[(bromoacetyl)amino]benzoate (2.72 g, 10.0mmol) in dimethylformamide (20 ml) was added 3-methoxypropylamine (1.78g, 20.0 mmol) and triethylamine (22.3 ml, 160 mmol). After stirring atroom temperature for 18 h, the reaction mixture was concentrated undervacuum and purified by flash chromatography (CH₂Cl₂/MeOH 9:0.4)affording 1.81 g (65%) of methyl4-({[(3-methoxy-propyl)amino]acetyl}amino)benzoate as a pale red solid.M.p.: 49-50° C., TLC (CH₂Cl₂/MeOH 9:1): R_(f) 0.36; ¹H-NMR (400 MHz,D₆-DMSO): 10.10 (br s, 1H), 7.92 (d, 8.7 Hz, 2H), 7.77 (d, 8.7 Hz, 2H),3.82 (s, 3H), 3.40-3.30 (m, 4H), 3.21 (s, 3H), 2.57 (t, 7.0 Hz, 2H),1.69-1.63 (m, 2H) (amine-H not observed); ESI-MS: [M+H⁺]=281.0

Example VIII Ethyl4-{3-[(tert-butoxycarbonyl)amino]-1-piperidinyl}benzoate

To a solution of ethyl 4-bromobenzoate (1.10 g, 4.80 mmol) in toluene(15 ml) was added tert-butyl 3-piperidinylcarbamate (1.16 g, 5.80 mmol),cesium carbonate (2.20 g, 6.70 mmol), palladium(II)acetate (35 mg, 156μmol) and (+/−)-2,2′-bis-(diphenylphosphino)-1,1′-binaphthaline (BINAP)(140 mg, 225 μmol). After stirring for 3 days at 100° C., the reactionmixture was diluted with tert-butylmethylether (25 ml) and was filtered.The filtrate was washed with brine, dried over MgSO₄, concentrated andpurified by flash chromatography (CH₂Cl₂/MeOH 99:0.6 then 99:1)affording 849 mg (51%) pale yellow solid. M.p.: 107-108° C., TLC(CH₂Cl₂/MeOH 9:0.2): R_(f) 0.66; ¹H-NMR (400 MHz, D₆-DMSO) 7.76 (d,J=8.9 Hz, 2H), 6.96-6.92 (m, 3H), 4.23 (q, J=7.1 Hz, 2H), 3.81-3.73 (m,2H), 3.41-3.35 (m, 1H), 2.88-2.72 (m, 2H), 1.84-1.70 (m, 2H), 1.50-1.40(m, 2H), 1.40 (s, 9H), 1.28 (t, J=7.1 Hz, 3H); EI-MS: [M⁺]=348.

Example IX Ethyl 4-(isobutylamino)benzoate

To a solution of ethyl 4-bromobenzoate (40.0 g, 175 mmol) in toluene(280 ml) was added iso-butylamine (15.3 g, 210 mmol), cesium carbonate(79.7 g, 244 mmol), palladium(II)acetate (290 mg, 1.31 mmol) and(+/−)-2,2′-bis-(diphenylphosphino)-1,1′-binaphthaline (BINAP) (1.30 g,1.96 mmol). After stirring for 1 day at 100° C., the same amounts ofpalladium(II)acetate and BINAP were added and stirring at 100° C. wascontinued for 4 days. The reaction mixture was diluted withtert-butylmethylether (100 ml) and was filtered. The filtrate was washedwith brine, dried over MgSO₄, concentrated and purified by flashchromatography (CH₂Cl₂/MeOH 9:0.3 then 9:0.5) affording 25.0 g (65%)white solid. M.p.: 57-58° C., TLC (CH₂Cl₂): R_(f) 0.44, ¹H-NMR (400 MHz,D₆-DMSO) 7.67 (d, J=8.8 Hz, 2H), 6.59-6.55 (m, 3H), 4.20 (q, J=7.1 Hz,2H), 2.88 (t, J=6.0 Hz, 2H), 1.88-1.78 (m, 1H), 1.26 (t, J=7.1 Hz, 3H),0.93, (d, J=6.7 Hz, 6H); ESI-MS: 222.2 [M+H]⁺.

Example X (2-anilino-1,3-benzoxazol-6-yl)acetic acid

To a stirred solution of 2-nitro-5-fluorophenole (44.4 g, 283 mmol) inacetonitrile (357 ml) was added potassium carbonate (39.1 g, 283 mmol).After dropwise addition of benzylbromide (50.8 g, 297 mmol), thereaction mixture was refluxed for 2 h. Water (1 l) was added and theresulting solution was extracted with tert-butylmethylether (4×). Thecombined organic layers were washed with brine, dried over MgSO₄ andevaporated, affording 68.9 g (99%) of2-(benzyloxy)-4-fluoro-1-nitrobenzene as a yellow solid: M.p. 64-65° C.;TLC (cyclohexane/ethyl acetate 8:2): R_(f) 0.50; ¹H-NMR (400 MHz,D₆-DMSO) 8.05 (dd, 9.1, 6.1 Hz, 1H), 7.49-7.36 (m, 6H), 7.03-6.98 (m,1H), 5.34 (s, 2H).

To a stirred solution of dimethyl malonate (123 g, 929 mmol) in1-methyl-2-pyrrolidon (554 ml) was added 60% sodium hydride in mineraloil (40.8 g, 1.02 mol) at room temperature. Stirring was continued untilno further gas was formed, and 2-(benzyloxy)-4-fluoro-1-nitrobenzene(140 g, 566 mmol) was added portionwise at room temperature. Afterstirring at 80° C. for 4 h, the reaction mixture was poured into icewater. The pH was adjusted to 7 by the addition of 5 M HCl, and thereaction mixture was extracted with ethyl acetate. The combined organiclayers were washed with water and brine, dried over MgSO₄ andevaporated. The residue was triturated with tert-butylmethyletheraffording 197 g (97%) of dimethyl2-[3-(benzyloxy)-4-nitrophenyl]malonate as a pale red viscous oil: TLC(cyclohexane/ethyl acetate 7:3): R_(f) 0.22; ¹H-NMR (400 MHz, D₆-DMSO)7.92 (d, 8.6 Hz, 1H), 7.51-7.35 (m, 6H), 7.15 (dd, 8.1, 1.5 Hz, 1H),5.28 (s, 2H), 5.22 (s, 1H), 3.70 (s, 6H); ESI-MS: [M−H]⁻=358.1.

Dimethyl 2-[3-(benzyloxy)-4-nitrophenyl]malonate (30.0 g, 83.5 mmol) wasdissolved in a mixture of acetic acid (200 ml) and concentratedhydrochloric acid (100 ml). Heating the reaction mixture to 100° C.resulted in an exothermic gas evolution, which ceased after 2.5 h.Evaporation of the solvent and drying in vacuum afforded 15.4 g (94%) of(3-hydroxy-4-nitrophenyl)acetic acid as a yellow viscous solid, whichwas employed in the next reaction step without further purification: TLC(cyclo-hexane/ethyl acetate/acetic acid 6:4:0.1): R_(f) 0.14, ¹H-NMR(400 MHz, D₆-DMSO) 12.58 (br s, 1H), 10.98 (s, 1H), 7.85 (d, 8.5 Hz,1H), 7.05 (d, 1.7 Hz, 1H), 6.88 (dd, 8.5, 1.7 Hz, 1H), 3.64 (s, 2H).

A solution of (3-hydroxy-4-nitrophenyl)acetic acid (14.0 g, 71.0 mmol)and concentrated sulfuric acid (6 ml) in methanol (300 ml) was refluxedfor 2 h. After addition of water (1 l), the solution was extracted withtert-butylmethylether (4×). The combined organic layers were washed withsaturated NaHCO₃ and brine, dried over MgSO₄ and evaporated. The residuewas triturated with petrol ether affording 11.0 g (73%) of methyl(3-hydroxy-4-nitrophenyl)acetate as a yellow solid: M.p. 56-57° C.; TLC(dichloromethane): R_(f) 0.46; ¹H-NMR (400 MHz, D₆-DMSO) 10.98 (s, 1H),7.86 (d, 8.5 Hz, 1H), 7.05 (d, 1.7 Hz, 1H), 6.88 (dd, 8.5, 1.7 Hz, 1H),3.76 (s, 2H), 3.63 (s, 3H); GC-MS (EI): [M]⁺=211.

Methyl (3-hydroxy-4-nitrophenyl)acetate (9.5 g, 45.0 mmol) was dissolvedin ethanol (150 ml). After addition of 10% Pd—C (0.95 g), the reactionmixture was hydrogenated at atmospheric pressure at room temperature.The catalyst was removed by filtration over celite. Concentrating thefiltrate to dryness afforded 7.92 g (97%) methyl(4-amino-3-hydroxyphenyl)acetate as a brown solid: M.p. 112-114° C.; TLC(dichloromethane): R_(f) 0.12; ¹H-NMR (400 MHz, D₆-DMSO) 8.98 (br s,1H), 6.56 (d, 1.8 Hz, 1H), 6.50 (d, 7.8 Hz, 1H), 6.42 (dd, 7.8, 1.8 Hz,1H), 4.45 (br s, 2H), 3.57 (s, 3H), 3.39 (s, 2H); GC-MS (EI): [M]+=181.

To a solution of methyl (4-amino-3-hydroxyphenyl)acetate (1.00 g, 5.52mmol) in ethanol (120 ml) was added dropwise phenylisothiocyanate (0.82g, 6.07 mmol) at room temperature. After stirring for 2.5 h,1,3-dicyclohexylcarbodiimide (1.71 g, 8.28 mmol) was added and thereaction mixture was heated to reflux for 3 h. The precipitate wasremoved by filtration. The filtrate was concentrated to dryness and theresidue was taken up in toluene. Undissolved material was removed byfiltration and the filtrate was concentrated to dryness. Purification byflash chromatography (cyclohexane/ethyl acetate 9:0.7->6:4) yielded 0.85g (55%) of methyl (2-anilino-1,3-benzoxazol-6-yl)acetate as a whitesolid: M.p. 155-157° C.; TLC (cyclohexane/-ethyl acetate 6:4): R_(f)0.38; ¹H-NMR (400 MHz, D₆-DMSO) 10.68 (s, 1H), 7.76 (d, 7.7 Hz, 2H),7.42-7.36 (m, 4H), 7.12 (dd, 8.0, 1.4 Hz, 1H), 7.05-7.02 (m, 1H), 3.76(s, 2H), 3.63 (s, 3H); ESI-MS: [M+H]⁺=282.9.

A solution of methyl (2-anilino-1,3-benzoxazol-6-yl)acetate (3.00 g,10.6 mmol) and potassium hydroxide (892 mg, 15.9 mmol) inmethanol/dioxane/water (200 ml/80 ml/200 ml) was stirred at roomtemperature for 4 h. The reaction mixture was diluted with water andwashed with tert-butylmethylether. The pH was adjusted to 3 by theaddition of 1 N hydrochloric acid. The precipitate was collected byfiltration and dried in vacuum affording 2.71 g (95%) of(2-anilino-1,3-benzoxazol-6-yl)acetic acid as a white solid: M.p.222-223° C.; TLC (dichloromethane/methanol/acetic acid 9:0.5:0.1): R_(f)0.44;. ¹H-NMR (400 MHz, D₆-DMSO): 12.20 (br s, 1H), 10.62 (s, 1H), 7.75(d, 7.8 Hz, 2H), 7.40-7.35 (m, 4H), 7.11 (d, 8.1 Hz, 1H), 7.05-7.01 (m,1H), 3.65 (s, 2H); ESI-MS: [M+H]⁺⁼268.9.

Example XI {2-[(2-methylphenyl)amino]-1,3-benzoxazol-6-yl}acetic acid

To a solution of methyl (4-amino-3-hydroxyphenyl)acetate (3.50 g, 19.3mmol) in ethanol (300 ml) was added dropwise o-tolylisothiocyanate (3.17g, 21.3 mmol) at room temperature. After stirring for 18 h,1,3-dicyclohexylcarbodiimide (5.98 g, 29.0 mmol) was added and thereaction mixture was heated to reflux for 3 h. The precipitate wasremoved by filtration. The filtrate was concentrated to dryness and theresidue was taken up in toluene. Undissolved material was removed byfiltration and the filtrate was concentrated to dryness. Purification byflash chromatography (cyclohexane/ethyl acetate 9:1->6:4) yielded 3.64 g(64%) of methyl {2-[(2-methylphenyl)amino]-1,3-benzoxazol-6-yl}acetateas a white solid. M.p.: 128-129° C.; TLC (cyclohexane/ethyl acetate6:4): R_(f) 0.38; ¹H-NMR (400 MHz, D₆-DMSO) 9.68 (s, 1H), 7.82 (d, 8.6Hz, 1H), 7.38 (d, 1.0 Hz, 1H), 7.30-7.23 (m, 3H), 7.10-7.07 (m, 2H),3.74 (s, 2H), 3.62 (s, 3H), 2.30 (s, 3H); ESI-MS: [M+H]⁺⁼296.9

A solution of methyl{2-[(2-methylphenyl)amino]-1,3-benzoxazol-6-yl}acetate (3.19 g, 10.8mmol) and potassium hydroxide (909 mg, 16.2 mmol) inmethanol/-dioxane/water (70 ml/70 ml/30 ml) was stirred at roomtemperature for 5 h. The reaction mixture was diluted with water andwashed with tert-butylmethylether. The pH was adjusted to 3 by theaddition of 1 N hydrochloric acid. The precipitate was collected byfiltration and dried in vacuum affording 2.76 g (91%) of{2-[(2-methylphenyl)amino]-1,3-benzoxazol-6-yl}acetic acid as a whitesolid. M.p.: 199-200° C.; TLC (cyclohexane/ethyl acetate 6:4): R_(f)0.08;. ¹H-NMR (400 MHz, D₆-DMSO) 9.65 (s, 1H), 7.82 (d, 9.1 Hz, 1H),7.35 (s, 1H), 7.29-7.24 (m, 3H), 7.10-7.06 (m, 2H), 3.62 (s, 2H), 2.30(s, 3H); ESI-MS: [+H]⁺=282.9.Compound Synthesis (In Solution)

Step AGeneral Procedure A1 (GP A1): Coupling of amines withBoc-L-leucin-N-carboxy-anhydride:

A solution/suspension of 1.0 eq. of the amine, 1.0 eq. ofBoc-L-leucin-N-carboxyanhydride and 0.3 eq. of4-(N,N′-dimethylamino)pyridine was refluxed for 0.5-14 days withexclusion of moisture. If a precipitate was formed, the precipitate(product) was collected by filtration. The reaction mixture/filtrate wasevaporated to dryness, redissolved in ethyl acetate and washed with 1 Naqueous HCl, saturated aqueous NaHCO₃ and brine, dried over MgSO₄ andevaporated. Both solids were combined. If necessary the product waspurified by trituration or by flash-chromatography or used withoutfurther purification.

Example 1 Methyl 4-({Boc-L-leucine}amino)benzoate

Methyl 4-aminobenzoate (0.75 g, 4.97 mmol) was dissolved in CH₂Cl₂ (7ml). After the addition of Boc-L-leucin-N-carboxyanhydride (1.28 g, 4.79mmol) and 4-(N,N′-dimethylamino)pyridine (180 mg, 1.49 mmol) thesolution was stirred under reflux for 4 days. The precipitate (product)was collected by filtration. The filtrate was evaporated to dryness,redissolved in ethyl acetate and washed with 1 N aqueous HCl, saturatedaqueous NaHCO₃ and brine, dried over MgSO4 and evaporated. CombinedYield: 1.35 (75%) white solid. M.p.: 72-73° C.; TLC (CH₂Cl₂/MeOH 9:0.1):R_(f) 0.52;. ¹H-NMR (400 MHz, D₆-DMSO) 10.32 (s, 1H), 7.93 (d, J=8.7 Hz,2H), 7.76 (d, J=8.7 Hz, 2H), 7.12 (d, J=7.7 Hz, 1H), 4.18-4.12 (m, 1H),3.83 (s, 3H), 1.69-1.36 (m, 3H), 1.38 (s, 9H), 0.91-0.88 (m, 6H);ESI-MS: [M+H]⁺=309.1.

General Procedure A2 (GP A2): Coupling of Amines with Carboxylic AcidsActivated by Iso-Butyl Chloroformate.

A solution of 1.0 eq. of the carboxylic acid derivative and 1.0 eq. ofN-methyl-morpholine in tetrahydrofurane was cooled to −15° C. and 1.0eq. of iso-butyl chloroformate was added dropwise. After 5 min at 0° C.,1.0 eq. of the amine in tetrahydrofurane was added at −15° C. Thesolution was stirred for 1 h at 0° C., 1-4 d at r.t. and was evaporated.The residue was redissolved in ethyl acetate, washed with 1 N aqueousHCl (2×), saturated aqueous NaHCO₃ and brine, dried over MgSO₄ andevaporated.

General Procedure A3 (GP A3): Synthesis of Disubstituted Amines

To a stirred solution of 4.0 eq. of the amine in DMF was added dropwisea solution of 1.0 eq of methyl 4-[(bromoacetyl)amino]benzoate (ExampleIV) in DMF at room temperature. After stirring for 48 h, the solvent wasevaporated. The residue was purified by flash chromatography.

Methyl 4-({N-[2-(2-pyridinyl)ethyl]glycyl}amino)benzoate

To a stirred solution of 2-(2-aminoethyl)pyridine (4.89 g, 40.0 mmol) inDMF (15 ml), was added dropwise, methyl 4-[(bromoacetyl)amino]benzoate(2.72 g, 10.0 mmol) in DMF (30 ml) at room temperature. After stirringfor 48 h at room temperature, the solvent was evaporated. The residuewas purified by flash chromatography (CH₂Cl₂/MeOH/NH₃ 9:0.05:0.1)affording 2.30 g (73%) of methyl4-({N-[2-(2-pyridinyl)ethyl]glycyl}amino)benzoate as a yellow oil. TLC(CH₂Cl₂/MeOH/NH₃ 9:1:0.1): R_(f) 0.60; ¹H-NMR (500 MHz, D₆-DMSO) 10.10(br s, 1H), 8.50-8.48 (m, 1H), 7.92 (d, J=8.8 Hz, 2H), 7.74-7.69 (m,3H), 7.30 (d, J=7.8 Hz, 1H), 7.24-7.21 (m, 1H), 3.84 (s, 3H), 3.36 (s,2H), 2.93-2.91 (m, 4H) (amine proton not observed); ESI-MS:[M+H]⁺=314.1. TABLE 1 33/57 Characterization of reaction productsaccording to Step A Example Procedure/ HPLC No. Structure (Startingmaterial) Yield [%] Product M.p. [° C.] ESI-MS t_(R)[min] 1

GP A1 (Example 1) 75 white solid 0.52 (CH₂Cl₂/MeOH 9:0.1) 72-73 309.1[M + H]⁺ n.d. 2

GP A2 (methyl 4-aminobenzoate & N²BOC-N⁶-FMOC-L-lysine 63 white solid0.58 (CH₂Cl₂/MeOH 9:0.5) 179-181 603 [M + H⁺ n.d. 3

as described in the precursor synthesis example IV 65 pale red solid0.36 (CH₂Cl₂/MeOH 9:1) 49-50 281.0 [M + H]⁺ n.d. 4

GP A2, (methyl 4- aminobenzoate & BOC- glycine) trituration with ethylacetate affords pure product 55 white solid 0.64 (CH₂Cl₂/MeOH 9:1)140-142 n.d. n.d. 5

same method as precursor synthesis: Example VIII (ethyl 4-bromobeuzoate& tert-butyl 3- pyrrolidinylcarbamate) 30 pale brown solid 0.62(CH₂Cl₂/MeOH 9:0.5) 128-129 335.3 [M + H]⁺ LC- MS 22.9 Method D 6

precursor synthesis: Example VIII 51 pale yellow solid 0.66 (CH₂Cl₂/MeOH9:0.2) 107-108 348 [M]⁺EI-MS n.d. 7

Example IX, then GP A1 (Boc-glycin-N- carboxyanhydride) FC: CH₂Cl₂/MeOH1:0-1:0.1, Purity: 40% by HPLC 14 pale brown foam 0.48 (CH₂Cl₂/MeOH9:0.2) n.d. 379.1 [M + H]⁺ LC- MS 24.3 Method A 8

precursor synthesis: Example IX, than same method as in precursorsynthesis: Example IV (bromoacetyl bromide & methoxypropylamine) 85 paleyellow oil 0.24 (CH₂Cl₂/MeOH/NH₃9:1:0.1) n.d. 351.5 [M + H]⁺ 20.9 MethodA 9

same method as in example IV (methyl 4- (methylamino)benzoate &bromoacetyl bromide, then GP A3 (methoxypropylamine) 93 yellow solid0.52 (CH₂Cl₂/MeOH/NH₃9:1:0.1) n.d. 294 [M]⁺GC-MS (EI) n.d. 10

GP A2 (methyl 4-aminobenzoate & N²-BOC-N⁶-FMOC-D-lysine) 92 white solid0.49 (CH₂Cl₂/MeOH 9:0.5) 175-176 603 [M + H]⁺FAB-MS 25.0 Method A 11

GP A3, FC CH₂Cl₂/NH₃9:0.1 (2-phenylethylamine & methyl 4-[(bromoacetyl)-amino]benzoate) 53 yellow solid 0.44 (CH₂Cl₂/MeOH 9:0.5) n.d. 313.1 [M +H]⁺ 18.3 Method A 12

GP A3, FC CH₂Cl₂/MeOH/NH₃9:0.05:0.1 (2-(2- pyridinyl)ethylamine & methyl4-[(bromoacetyl)- amino]benzoate) 73 yellow oil 0.60(CH₂Cl₂/MeOH/NH₃9:1:0.1) n.d. 314.1 [M + H]⁺ n.d. 13

GP A3, FC CH₂Cl₂/MeOH/NH₃9:0.05:0.1 (2-(3,5- dimethoxyphenyl)ethylamine& methyl 4-[(bromoacetyl)- amino]benzoate) 95 brown oil 0.70(CH₂Cl₂/MeOH 9:0.5) n.d. 373.0 [M + H]⁺ n.d. 14

GP A3, FC CH₂Cl₂/MeOH/NH₃9 9:0.05:0.1 (2-(3- chlorophenyl)ethylamine &methyl 4-[(bromoacetyl)- amino]benzoate) 89 brown oil 0.34 (hexane/ethylacetate) n.d. 347.0 [M + H]⁺ 19.5 Method A 15

GP A3, FC CH₂Cl₂/MeOH/NH₃9:0.01:0.1 (2-(3,4- dichlorophenyl)ethylamine &methyl 4-[(bromoacetyl)- amino]benzoate) 96 yellow oil 0.48 (CH₂Cl₂/MeOH9:0.5) n.d. 380.9 [M + H]⁺ 20.1 Method A 16

GP A3, FC Cyclohexane/ Ethyl acetate 8:2, 7:3 (2-[4-(4-chlorophenoxy)phenyl]- ethylamine & methyl 4-[(bromoacetyl)amino]benzoate) 61 brown oil 0.40 (CH₂Cl₂/MeOH/AcOH9.5:0.5:0.1) n.d. 439.0 [M + H]⁺ n.d.Step BGeneral Procedure B (GP B): Cleavage of the Boc-Protecting Group withTrifluoro-Acetic Acid

To a solution of the Boc-protected amine was added 20 vol %trifluoroacetic acid in dichloromethane at 0° C. Stirring was continuedat room temperature for 0.5-24 h. The solvent was removed at roomtemperature under reduced pressure. The residue was coevaporated twicewith dichloromethane, dried under high vacuum and subjected to thereaction step C without further purification.

Step C

General Procedure (GP Cl): Coupling of Amines with2-{4-[(2-toluidinocarbonyl)-amino]phenyl}acetic acid:

A solution of 1.0 eq. 2-{4-[(2-toluidinocarbonyl)amino]phenyl}aceticacid, 1.1 eq. HOBt and 1.1 eq. EDCI in DMF was stirred for 2 h at r.t.After addition of 1.0 eq. amine e.g. as TFA salt and 3-9 eq.ethylisopropylamine stirring was continued for 18 h at r.t. The reactionmixture was poured into the 4-fold amount of water. The precipitate wascollected by filtration, washed with cold water and dried in vacuum. Ifnecessary the product was purified by trituration or byflash-chromatography.

Methyl4-([({4-[(2-toluidinocarbonyl)amino]phenyl}acetyl)L-leucin]amino)-benzoate

Methyl 4-[(L-leucin)amino]benzoate trifluoroacetate (3.81 g, 10.1 mmol)was reacted according to GP C1 in a total volume of 60 ml ofdimethylacetamide. Trituration with CH₂Cl₂ yielded 4.78 g (90%) palebrown solid. M.p. 250-252° C., TLC (AcOH:MeOH:CH₂Cl₂ 0.1:0.5:9): R_(f)0.46; ¹H-NMR (400 MHz, D₆-DMSO):10.47 (s, 1H), 8.96 (s, 1H), 8.39 (d,7.7 Hz, 1H), 7.93-7.89 (m, 3H), 7.83 (d, 7.8 Hz, 1H), 7.75 (d, 8.8 Hz,2H), 7.37 (d, 8.4 Hz, 2H), 7.18-7.12 (m, 4H), 6.95-6.92 (m, 1H),4.49-4.43 (m, 1H), 3.82 (s, 3H), 3.47-3.38 (m, 2H), 2.24 (s, 3H),1.66-1.50 (m, 3H), 0.92 (d, 6.4 Hz, 3H), 0.86 (d, 6.4 Hz, 3H); ESI-MS:531.3 [M+H]⁺. TABLE 2 The following examples were prepared bysubsequently applying the general procedures B & C1/C2 as indicated. Ex-am- Procedure/ ple (Starting Yield HPLC No. Structure material) [%]Product R_(r) M.p.[° C.] ESI-MS t_(R)[min] 17

1) GP B 2) GP Cl, 9 eq. DIPEA/ (1 & example 1) 90 pale brown solid 0.46(CH₂Cl₂/MeOH/AcOH 9:0.5:0.1) 250-252 531.3 [M + H]⁺ 26.6 Method A 18

1) GP B 2) GP Cl, 9 eq. DIPEA (2 & example 1) FMOC is cleaved duringstep C1 crude product was em ployed in next step yellow solid 0.86(CH₂Cl₂/MeOH 9:1.5) n.d. 546 [M + H]⁺ n.d. 19

1) GP B 2) GP Cl, 3 eq. DIPEA (2 & example 1) 64 white solid 0.50(CH₂Cl₂/MeOH 9:1) 197-198 547.0 [M + H]⁺ 21.8 Method A 20

1) GP B 3) GP Cl, 9 eq DIPEA (4 & example 1) 96 pale brown solid 0.30(CH₂Cl₂/MeOH 9:1) 248-250 515.5 [M + H]⁺ 22.6 Method A 21

1) GP B 3) GP Cl, 9 eq DIPEA (7 & example 1) 14 pale yellow oil 0.56(CH₂Cl₂/MeOH 9:1) — 545.0 [M + H]⁺ n.d. 22

GP Cl, 3 eq DIPEA (8 & example 1) 43 pale yellow solid 0.82 (CH₂Cl₂/MeOH9:1) 123-125 617.6 [M + H]⁺ n.d. 23

GP Cl, 3 eq DIPEA (9 & example 1) 43 pale brown oil 0.74 (CH₂Cl₂/MeOH9:1) n.d. 561.2 [M + H]⁺ n.d. 24

1) GP B 2) GP Cl, 9 eq DIPEA (10 & example 1), FMOC is cleaved duringstep C1 crude product was em- ployed in next step pale brown solid 0.86(CH₂Cl₂/MeOH 9:1.5) n.d. 546.5 [M + H]⁺LC-MS n.d. 25

1) GP B 3) GP Cl, 3 eq DIPEA (4 & example X) 79 pale brown solid 0.30(CH₂Cl₂/MeOH 9:0.5) 235-237 459.0 [M + H]⁺ 20.3 Method A 26

GP Cl, 3 eq DIPEA (11 & example X) 85 white solid 0.46 (CH₂Cl₂/MeOH9:0.5) 110-112 563.1 [M + H]⁺ 23.2 Method A 27

GP Cl, 3 eq DIPEA (12 & example X) 62 white solid 0.16 (CH₂Cl₂/MeOH9:0.5) 102-104 564.2 [M + H]⁺ 20.0 Method A 28

GP Cl, 3 eq DIPEA (13 & example X) 90 pale brown solid 0.82 (CH₂Cl₂/MeOH9:1) 111-113 623.1 [M + H]⁺ 23.1 Method A 29

GP Cl, 3 eq DIPEA (14 & example X) 93 pale yellow solid 0.82(CH₂Cl₂/MeOH 9:1) 110-112 597.06 [M + H]⁺ 23.7 Method A 30

GP Cl, 3 eq DIPEA (15 & example X) 85 pale yellow solid 0.70(CH₂Cl₂/MeOH/AcOH 9:1:0.1) 89-91 631.0 [M + H]⁺ 24.7 Method A 31

GP Cl, 3 eq DIPEA (16 & example X) 33 white solid 0.72 (CH₂Cl₂/MeOH 9:1)173-174 689.4 [M + H]⁺LC-MS 21.9 Method A 32

GP Cl, 3 eq DIPEA (4 & example XI) 78 pale brown solid 0.91(CH₂Cl₂/MeOH/AcOH 9:1:0.1) 156-158 473.3 [M + H]⁺LC-MS 19.7 Method A 33

GP Cl, 3 eq DIPEA (11 & example XI 88 white solid 0.95 (CH₂Cl₂/MeOH/AcOH9:1:0.1) 100-105 577.1 [M + H]⁺ 22.8 Method A 34

GP Cl, 3 eq DIPEA (12 & example XI 93 yellow solid 0.40 (CH₂Cl₂/MeOH9:0.5)  99-100 578.1 [M + H]⁺ 19.5 Method A 35

1) GP B 2) GP Cl, 9 eq DIPEA (6 & example 1) 89 pale brown solid 0.46(CH₂Cl₂/MeOH 9:1) 225-227 475.04 [M + H]⁺ 20.2 Method A 36

1) GP B 2) GP Cl, 9 eq DIPEA (5 & example 1) 94 white solid 0.74(CH₂Cl₂/MeOH 9:1) 150-153 501.0 [M + H]⁺ 22.7 Method AStep DGeneral Procedure D1 (GP DI): Ester Saponification

A solution or suspension of the ester and 1.1-10 eq eq. of KOH inwater/ethanol or methanol and/or dioxane was stirred at 25-50° C. for2-48 h. After washing with tert-butylmethylether (80 ml) the volume ofthe reaction mixture was reduced until a slight turbidity was observed.The solution was acidified to pH 2 by the addition of 1 N aqueous HCl.The precipitate was collected by filtration, washed with cold water anddried in vacuum.

General Procedure D2 (GP D2): Deprotection of Benzyl Esters/BenzylCarbamates

A solution or suspension of the ester and 10% Pd—C (10%) indimethylformamide was hydrogenated for 12 h at r.t. and 50 bar hydrogenpressure. The reaction mixture was filtered through celite. Evaporationof the filtrate and purification of the crude product by preparativeHPLC (LiChrospher RP-18, 12 μM, 250×25 mm; flow rate 40 ml/min; eluent:acetonitrile/water mixture with 0.1% trifluoroacetic acid (vol./vol.),linear gradient of: 0 min. =40% acetonitrile, 20 min. =80% acetonitrile)afforded the product.

General Procedure D3 (GP D3): Deprotection of Benzyl Esters

A solution or suspension of the ester and 10% Pd—C (10%) intetrahydrofurane was hydrogenated for 18 h at r.t. under atmospherichydrogen pressure. The reaction mixture was filtered through celite.Evaporation of the filtrate afforded the product.

General Procedure D4 (GP D4): Deprotection of Tert-Butyl Esters

A solution of the ester in 20% trifluoroacetic acid in methylenechloride(v/v) was stirred at room temperature. The solvent was evaporated andthe residue was dried in high vacuum. If necessary, the product waspurified by trituration (e.g. in CH₂Cl₂/MeOH) or by flashchromatography.

General Procedure Solid Phase Compound Synthesis SPS1 (GP SPS1):

Synthesis Scheme SPS1:

Step a: Wang polystyrene resin (1.5 g, Rapp-Polymere, Tübingen; loading0.96 mmol/g) was swollen in tetrahydrofuran. The solvent was filteredoff with suction and a solution of 737 mg diisopropyethylamine (737 mg)in tetrahydrofuran (4.5 ml) and a solution of 4-nitrobenzoicacidchloride (945 mg) in tetrahydrofuran (3.5 ml) was added. Aftershaking overnight at room temperature, the derivatized resin wassubsequently washed with dimethylformamide, methanol, tetrahydrofuranand dichloromethane.

Step b: The derivatized resin was treated with a solution of tin(II)chloride dihydrate (2.7 g) in N-methylpyrrolidone (6 ml) and was shakenovernight at room temperature. The resin was subsequently washed withN-methylpyrrolidone, methanol, tetrahydrofuran and dichloromethane.

Step c: To a solution of the 9-fluorenylmethoxycarbonyl (Fmoc) protectedamino acid (2.0 eq) in dimethylformamide (7 ml),O-(7-azabenzotriazol-1-yl)1,1,3,3-tetra-methyluroniumhexafluorophosphate (1.06 g) and diisopropylethylamin (488 μl) wereadded. After shaking for 15 minutes, the derivatized resin was treatedwith this solution for 4 hours at room temperature. The derivatizedresin was subsequently washed with dimethylformamide andtetrahydrofurane.

Step d: The derivatized resin was treated with 20% piperidine indimethylformamide (15 ml, v/v) and was shaken at room temperature for 10minutes. After washing 3 times with dimethylformamide, further 20%piperidine in dimethylformamide (15 ml, v/v) was added. After shakingfor 20 minutes, the resin was subsequently washed with dimethylformamideand tetrahydrofurane. To a solution of2-{4-[(2-toluidinocarbonyl)amino]phenyl}acetic acid (0.9 g, example I)in dimethylformamide (8 ml),O-(7-azabenzotriazol-1-yl)1,1,3,3-tetramethyluroniumhexafluoro-phosphate (1.2 g) and diisopropylethylamin (557 μl) wereadded. After shaking the mixture for 15 minutes, the derivatized resinwas treated with this solution for 4 hours at room temperature. Thederivatized resin was subsequently washed with dimethylformamide andtetrahydrofurane.

Step e: For removal of the product from the resin, the derivatized resinwas shaken with 10 ml of trifluoroacetic acid/dichloromethane 1:1 (v/v)for 1 hour and was filtered off. The filtrate was concentrated underreduced pressure and purified on silica gel.

General Procedure Solid Phase Compound Synthesis SPS2 (GP SPS2):

Synthesis Scheme SPS2:

Step a: Wang polystyrene resin (1.5 g, Rapp-Polymere, Tübingen; loading0.96 mmol/g) was swollen in tetrahydrofuran. The solvent was filteredoff with suction and a solution of diisppropyethylamine (737 mg) intetrahydrofuran (4.5 ml) and a solution of 4-nitrobenzoic acidchloride(945 mg) in tetrahydrofuran (3.5 ml) was added. After shaking overnightat room temperature, the derivatized resin was subsequently washed withdimethylformamide, methanol, tetrahydrofuran and dichloromethane.

Step b: The derivatized resin was treated with a solution of tin(II)chloride dihydrate (2.7 g) in N-methylpyrrolidone (6 ml) and was shakenovernight at room temperature. The resin was subsequently washed withN-methylpyrrolidone, methanol, tetrahydrofuran and dichloromethane.

Step c: A solution of bromoacetic acid (990 mg) in dimethylformamide (11ml) was added to the derivatized resin. After shaking for 1 minute, asolution of diisopropyl-carbodiimide (1.26 g) in dimethylformamide (3ml) was added. Following shaking over night, the derivatized resin wassubsequently washed with dimethylformamide, methanol anddichloromethane.

Step d: A 1.8 molar solution of the amine derivative (8 ml) indimethylformamide and diisopropylethylamine (0.8 g) was added to thederivatized resin. After shaking over night, the derivatized resin wassubsequently washed with dimethylformamide, methanol anddichloromethane.

Step e: To a solution of 2-{4-[(2-toluidinocarbonyl)amino]phenyl}aceticacid (0.9 g, example I) in dimethylformamide (8 ml),O-(7-azabenzotriazol-1-yl)1,1,3,3-tetra-methyluroniumhexafluorophosphate (1.2 g) and diisopropylethylamin (557 μl) wereadded. After shaking the mixture for 15 minutes, the derivatized resinwas treated with this solution for 4 hours at room temperature. Thederivatized resin was washed with dimethylformamide andtetrahydrofurane.

Step f: For removal of the product from the resin, the derivatized resinwas shaken with 10 ml of trifluoroacetic acid/dichloromethane 1:1 (v/v)for 1 hour and was filtered off. The filtrate was concentrated underreduced pressure and purified on silica gel.

General Procedure Solid Phase Compound Synthesis SPS3 (GP SPS3):

Synthesis Scheme SPS3:

Step a: Wang polystyrene resin (1.5 g, Rapp-Polymere, Tübingen; loading0.96 mmol/g) was swollen in tetrahydrofuran. The solvent was filteredoff with suction and a solution of 737 mg diisopropyethylamine (737 mg)in tetrahydrofuran (4.5 ml) and a solution of 4-nitrobenzoicacidchloride (945 mg) in tetrahydrofuran (3.5 ml) was added. Aftershaking overnight at room temperature, the derivatized resin wassubsequently washed with dimethylformamide, methanol, tetrahydrofuranand dichloromethane.

Step b: The derivatized resin was treated with a solution of tin(II)chloride dihydrate (2.7 g) in N-methylpyrrolidone (6 ml) and was shakenovernight at room temperature. The resin was subsequently washed withN-methylpyrrolidone, methanol, tetrahydrofuran and dichloromethane.

Step c: To a solution of the 9-fluorenylmethoxycarbonyl (Fmoc) protectedamino acid (2.0 eq) in dimethylformamide (7 ml),O-(7-azabenzotriazol-1-yl)1,1,3,3-tetra-methyluroniumhexafluorophosphate (1.06 g) and diisopropylethylamin (488 μl) wereadded. After shaking for 15 minutes, the derivatized resin was treatedwith this solution for 4 hours at room temperature. The derivatizedresin was subsequently washed with dimethylformamide andtetrahydrofurane.

Step d: The derivatized resin was treated with 20% piperidine indimethylformamide (15 ml, v/v) and was shaken at room temperature for 10minutes. After washing 3 times with dimethylformamide, further 20%piperidine in dimethylformamide (15 ml, v/v) was added. After shakingfor 20 minutes, the resin was subsequently washed with dimethylformamideand tetrahydrofurane. To a solution of(2-anilino-1,3-benzoxazol-6-yl)acetic acid (0.9 g, example X) indimethylformamide (8 ml),0-(7-azabenzotriazol-1-yl)1,1,3,3-tetramethyluronium hexafluorophosphate(1.2 g) and diisopropylethylamin (557 μl) were added. After shaking themixture for 15 minutes, the derivatized resin was treated with thissolution for 4 hours at room temperature. The derivatized resin wassubsequently washed with dimethylformamide and tetrahydrofurane.

Step e: For removal of the product from the resin, the derivatized resinwas shaken with 10 ml of trifluoroacetic acid/dichloromethane 1:1 (v/v)for 1 hour and was filtered off. The filtrate was concentrated underreduced pressure and purified on silica gel.

General Procedure Solid Phase Compound Synthesis SPS4 (GP SPS4):

Synthesis Scheme SPS4:

Step a: Wang polystyrene resin (1.5 g, Rapp-Polymere, Tübingen; loading0.96 mmol/g) was swollen in tetrahydrofuran. The solvent was filteredoff with suction and a solution of diisopropyethylamine (737 mg) intetrahydrofuran (4.5 ml) and a solution of 4-nitrobenzoic acidchloride(945 mg) in tetrahydrofuran (3.5 ml) was added. After shaking overnightat room temperature, the derivatized resin was subsequently washed withdimethylformamide, methanol, tetrahydrofuran and dichloromethane.

Step b: The derivatized resin was treated with a solution of tin(II)chloride dihydrate (2.7 g) in N-methylpyrrolidone (6 ml) and was shakenovernight at room temperature. The resin was subsequently washed withN-methylpyrrolidone, methanol, tetrahydrofuran and dichloromethane.

Step c: A solution of bromoacetic acid (990 mg) in dimethylformamide (11ml) was added to the derivatized resin. After shaking for 1 minute, asolution of diisopropylcarbodiimide (1.26 g) in dimethylformamide (3 ml)was added. Following shaking over night, the derivatized resin wassubsequently washed with dimethyl-formamide, methanol anddichloromethane.

Step d: A 1.8 molar solution of the amine derivative (8 ml) indimethylformamide and diisopropylethylamine (0.8 g) was added to thederivatized resin. After shaking over night, the derivatized resin wassubsequently washed with dimethylformamide, methanol anddichloromethane.

Step e: To a solution of (2-anilino-1,3-benzoxazol-6-yl)acetic acid (0.9g, example X) in dimethylformamide (8 ml), O-(7-azabenzotriazol-1-yl),1,3,3-tetramethyluronium hexafluorophosphate (1.2 g) anddiisopropylethylamin (557 μl) were added. After shaking the mixture for15 minutes, the derivatized resin was treated with this solution for 4hours at room temperature. The derivatized resin was washed withdimethylformamide and tetrahydrofurane.

Step f: For removal of the product from the resin, the derivatized resinwas shaken with 10 ml of trifluoroacetic acid/dichloromethane 1:1 (v/v)for 1 hour and was filtered off. The filtrate was concentrated underreduced pressure and purified on silica gel. TABLE 3 The followingexamples were prepared according to the general procedures D1-D4, SPS1-4: Procedure/ Example (Starting Yield No. Structure material) [%]Product R_(f) M.p. [° C.] ESI-MS HPLC t_(R)[min] 37

GP D1; 10 eq. KOH (17) 90 white solid 0.24 (CH₂Cl₂/MeOH/Ac OH 9:1:0.1)219-223 517.0 [M + H]⁺ 21.3 Method A 38

GP D1; 1.1 eq. KOH (19) 76 white solid 0.48 (CH₂Cl₂/MeOH/AcOH 9:1:0.1)210-218 570.8 [M + K]⁺ 20.0 Method A 39

GP D1, 1.1 eq. KOH (20) 87 pale brown solid 0.24 (CH₂Cl₂MeOH/AcOH9:1:0.1) 268-271 460.9 [M + H]⁺ 18.2 Method A 40

SPS1 n.d. n.d. n.d. n.d. 504.2 [M + H]⁺ 5.7 Method C 41

SPS1 n.d. n.d. n.d. n.d. 518.2 [M + H]⁺ 5.7 Method C 42

SPS1 n.d. n.d. n.d. n.d. 519.1 [M + H]⁺ 6.5 Method C 43

SPS1 n.d. n.d. n.d. n.d. 590.2 [M + H]⁺ 8.5 Method C 44

SPS1 n.d. n.d. n.d. n.d. 552.2 [M + H]⁺ 6.0 Method C 45

SPS1 n.d. n.d. n.d. n.d. 552.1 [M + H]⁺ 6.1 Method C 46

SPS1 n.d. n.d. n.d. n.d. 558.1 [M + H]⁺ 7.3 Method C 47

SPSl n.d. n.d. n.d. n.d. 541.2 [M + H]⁺ 5.9 Method C 48

SPS1 n.d. n.d. n.d. n.d. 516.2 [M + H]⁺ 5.9 Method C 49

GP D1, 1.1 eq. KOH (35) 36 white solid 0.44 (CH₂Cl₂/MeOH 9:1) 236-238487.0 [M + H]⁺ 19.8 Method A 50

GP D1, 1.1 eq. KOH (36) 8 pale brown solid 0.42 (CH₂Cl₂/MeOH 9:1)239-242 473.0 [M + H]⁺ 19.4 Method A 51

GP D1, 1.1 eq. KOH (21) 64 white solid 0.70 (CH₂Cl₂/MeOH/AcOH 9:1:0.1)131-132 517.3 [M + H]⁺ 20.6 Method A 52

GP D1, 1.1 eq. KOH (22) 96 white solid 0.12 (CH₂Cl₂/MeOH/AcOH9.5:0.5:0.1) 76.0-76.5 589.3 [M + H⁺ 20.9 Method A 53

GP D1, 1.1 eq. KOH (23) 77 pale yellow solid 0.08 (CH₂Cl₂/MeOH/AcOH9.5:0.5:0.1) 63-64 547.2 [M + H]⁺ 19.2 Method A 53a

GP D2 (18) 3 white solid 0.05 (CH₂Cl₂/MeOH/AcOH 9:1:0.1) 168-169 532.1[M + H]⁺LC-MS n.d. 54

GP D1, 4 eq. KOH (24) 45 white solid 0.06 (CH₂Cl₂/MeOH 9:15) 73-75 532.3[M + H]⁺ 17.7 Method A 55

SPS2 n.d. n.d. n.d. n.d. 532.2 [M + H]⁺ 6.2 Method C 56

SPS2 n.d. n.d. n.d. n.d. 546.2 [M + H]⁺ 5.9 Method C 57

SPS2 n.d. n.d. n.d. n.d. 572.3 [M + ACN]⁺ 5.7 Method C 58

SPS2 n.d. n.d. n.d. n.d. 572.3 [M + H]⁺ 6.3 Method C 59

SPS2 n.d. n.d. n.d. n.d. 572.3 [M + H]⁺ 6.6 Method C 60

SPS2 n.d. n.d. n.d. n.d. 663.3 [M + H]⁺ 7.6 Method C 61

SPS2 n.d. n.d. n.d. n.d. 545.1 [M + H]⁺ 7.9 Method C 62

SPS2 n.d. n.d. n.d. n.d. 558.2 [M + H]⁺ 5.7 Method C 63

SPS2 n.d. n.d. n.d. n.d. 546.2 [M + H]⁺ 6.1 Method C 64

SPS2 n.d. n.d. n.d. n.d. 558.2 [M + H]⁺ 6.0 Method C 65

SPS2 n.d. n.d. n.d. n.d. 503.1 [M + H]⁺ 8.0 Method C 66

SPS2 n.d. n.d. n.d. n.d. 586.2 [M + H]⁺ 7.1 Method C 67

SPS2 n.d. n.d. n.d. n.d. 519.1 [M + H]⁺ 7.4 Method C 68

SPS2 n.d. n.d. n.d. n.d. 588.2 [M + H]⁺ 5.8 Method C 69

SPS2 n.d. n.d. n.d. n.d. 552.1 [M + H]⁺ 5.9 Method C 70

SPS2 n.d. n.d. n.d. n.d. 552.1 [M + H]⁺ 6.2 Method C 71

SFS2 n.d. n.d. n.d. n.d. 552.1 [M + H]⁺ 5.8 Method C 72

SPS2 n.d. n.d. n.d. n.d. 555.2 [M + H]⁺ 5.7 Method C 73

SPS2 n.d. n.d. n.d. n.d. 566.1 [M + H]⁺ 6.0 Method C 74

GP D1; 2.1 eq KOH (25) 85 white solid 0.06 (CH₂Cl₂/MeOH/AcOH9:1:0.1) >280 445.0 [M + H]⁺ 18.6 Method D 75

GP D1; 1.1 eq KOH (26) 62 white solid 0.40 (CH₂Cl₂/MeOH/AcOH 9:0.5:0.1)160-162 549.1 [M + H]⁺ 21.6 Method A 76

GP D1; 2.1 eq KOH (27) 98 white solid 0.08 (CH₂Cl₂/MeOH/AcOH 9:0.5:0.1)252-253 550.1 [M + H]⁺ 18.0 Method A 77

GP D1; 1.1 eq KOH (28) 66 whit solid 0.32 (CH₂Cl₂/MeOH/AcOH 9:0.5:0.1)130-13  609.1 [M + H]⁺ 20.5 Method D 78

GP D1; 1.1 eq KOH (29) 96 white solid 0.32 (CH₂Cl₂/MeOH/AcOH 9:0.5:0.1)162-165 583.0 [M + H]⁺ 22.5 Method A 79

GP D1; 1.1 eq KOH (30) 79 pale brown solid 0.26 (CH₂Cl₂/MeOH/AcOH9:0.5:0.1) 170-171 616.9 [M + H]⁺ 23.2 Method A 80

GP D1; 1.1 eq KOH (31) 89 pale brown solid 0.56 (CH₂Cl₂/MeOH/AcOH9:0.5:0.1) 156-158 675.0 [M + H]⁺ 23.4 Method D 81

GP D1; 2 eq KOH (32) 89 pale red 0.16 (CH₂Cl₂/MeOH/AcOH 9:0.5:0.1)267-268 459.0 [M + H]⁺ 16.4 Method A 82

GP D1; 2 eq KOH (33) 86 white solid 0.32 (CH₂Cl₂/MeOH/AcOH 9:0.5:0.1)232-233 563.0 [M + H]⁺ 19.9 Method D 83

GP D1; 2 eq KOH (34) 30 white solid 0.18 (CH₂Cl₂/MeOH/AcOH 9:0.5:0.1)175-176 546.8 [M + H]⁺ 16.4 Method D 84

GP SPS4 n.d. n.d. n.d. n.d. 556.36 [M + H]⁺ 6.1 Method C 85

GP SPS2 n.d. n.d. n.d. n.d. 593.36 [M − H]⁺ 9.1 Method C 86

GP SPS2 n.d. n.d. n.d. n.d. 549.34 [M − H]⁺ 8.8 Method C 87

GP SFS4 n.d. n.d. n.d. n.d. 579.38 [M + H]⁺ 9.1 Method C 88

GP SPS1 n.d. n.d. n.d. n.d. 551.21 [M + H]⁺ 8.7 Method C 89

GP SFS3 n.d. n.d. n.d. n.d. 535.22 [M + H]⁺ 8.8 Method C 90

GP SF51 n.d. n.d. n.d. n.d. 630.19 [M + H]⁺ 9.3 Method C 91

GP SPS3 n.d. n.d. n.d. n.d. 613.18 [M + H]⁺ 9.4 Method C 92

GP SPS4 n.d. n.d. n.d. n.d. 535.35 [M + H]⁺ 8.8 Method CIn Vitro Assay: Adhesion of Ramos Cells to Immobilized VCAM-1 (Domains1-3)Preparation of VCAM-1 (Extracellular Domains 1-3)

Complementary DNA (cDNA) encoding 7-domain form of VCAM-1 (GenBankaccession #M60335) was obtained using Rapid-Screen™ cDNA library panels(OriGene Technologies, Inc) at Takara Gene Analysis Center (Shiga,Japan). The primers used were 5′-CCA AGG CAG AGT ACG CAA AC-3′ (sense)and 5′-TGG CAG GTA TTA TTA AGG AG-3′ (antisense). PCR amplification ofthe 3-domain VCAM-1 cDNA was perform using Pfu DNA polymerase(Stratagene) with the following sets of primers: (U-VCAMd1-3) 5′-CCA TATGGT ACC TGA TCA ATT TAA AAT CGA GAC CAC CCC AGA A-3′; (L-VCAMdl-3) 5-CCATAT AGC AAT CCT AGG TCC AGG GGA GAT CTC AAC AGT AAA-3′. PCR cycle was94° C. for 45 sec, 55° C. for 45 sec, 72° C. for 2 min, repeating 15cycles. After the purification of the PCR product, the fragment wasdigested with KpnI-AvrII. The digested fragment was ligated intopBluescript IISK(−) (Strategene), which was linearized by digesting withKpnI-XhoI. The ligation was followed by transformation to a Dam/Dcmmethylase-free E. coli strain SCS110 (Strategene) to create the donorplasmid pHH7. To direct VCAM-1 molecule into the insect cell secretorypathway, the VCAM-1 coding sequence was fused to signal peptide sequenceof honeybee melittin. The resulting melittin-VCAM fusion was placed incorrect orientation to the baculovirus polyhedrin promoter. Baculovirustransfer vector containing first 3-domain form VCAM-1 (pH10) wasconstructed by ligation of 0.9 kb fragment from AvrII/Klenow/BclIdigests of pH7 into SalI/Klenow/BamHI digests of pMelBacB (Invitrogen).Recombinant baculovirus was generated by using Bac-N-Blue™ Transfectionkit (Invitrogen) according to the manufacture's instruction. Therecombinant virus was amplified by infection to High-Five™ insect cellsfor 5-6 days, and virus titer was determined by plaque assay.

High-Five™ insect cells were pelleted in a 225 ml conical tube bycentrifugation at 1000 rpm for 5 min. After discarding the supernatant,the pellet was resuspended in 1.5×10⁹ pfu (MOI=5) of high-titer virussolution, followed by incubation for 1.5 hours at room temperature. Thecells were pelleted again and washed once in fresh Express Five™ serumfree medium. The cells were pelleted again and finally, resuspended in200 ml of fresh Express Five TM medium, transferred to a 1,000 ml shakerflask, and incubated in a shaker at 27° C., 130 rpm, for 48 hours beforethe culture supernatant was collected. The purification of 3-domain formof VCAM-1 from the culture supernatant was performed by one-step anionexchange chromatography. Protein concentration was determined by usingCoomassie protein assay reagent (Pierce) according to the manufacture'sinstruction.

Preparation of VCAM-1 Coated Microtiter Plates

Recombinant human VCAM-1 (extracellular domains 1-3) was dissolved at1.0 μg/ml in PBS. Each well of the microtiter plates (Nalge NuncInternational, Fluoronunc Cert, 437958) was coated with 100 μl ofsubstrate or for background control with buffer alone for 15 hours at 4C. After discarding the substrate solution, the wells were blocked using150 μl per well of block solution (Kirkegaard Perry Laboratories,50-61-01) for 90 minutes. The plate was washed with wash buffercontaining 24 mM Tris-HCl (pH 7.4), 137 mM NaCl, 27 mM KCl and 2 mMMnCl₂ just before addition of the assay.

In Vitro Assay using Ramos Cells

Preparation of Fluorescence Labeled Ramos Cells:

Ramos cells (American Type Culture Collection, Clone CRL-1596) werecultured in RPMI 1640 medium (Nikken Bio Medical Laboratory, CM1101)supplemented with 10% fetal bovine serum (Hyclone, A-1119-L), 100 U/mlpenicilin (Gibco BRL, 15140-122) and 100 μg/ml streptomycin (Gibco BRL,15140-122) in a humidified incubator at 37° C. with 5% CO₂.

Ramos cells were incubated with phosphate balanced solution (PBS,Nissui, 05913) containing 25 μM of 5(-and 6)-carboxyfluoresceindiacetate, succinimidyle ester (CFSE, Dojindo Laboratories, 345-06441)for 20 min at room temperature while gently swirling every 5 min. Aftercentrifugation at 1000 rpm for 5 min, the cell pellet was resuspendedwith adhesion assay buffer at a cell density of 4×10⁶ cells/ml. Theadhesion assay buffer was composed of 24 mM Tris-HCl (pH 7.4), 137 mMNaCl, 27 mM KCl, 4 mM glucose, 0.1% bovine serum albumin (BSA, Sigrna,A9647) and 2 mM MnCl₂.

Assay Procedure (Ramos Cells)

The assay solution containing each test compounds or 5 μg/ml anti-CD49dmonoclonal antibody (Immunotech, 0764) was transferred to the VCAM-1coated plates. The final concentration of each test compounds was 5 μM,10 μM or various concentrations ranging from 0.0001 μM to 10 μM using astandard 5-point serial dilution. The assay solution containing thelabeled Ramos cells was transferred to the VCAM-1 coated plates at acell density of 2×10⁵ cells per well and incubated for 1 hour at 37 C.The non-adherent cells were removed by washing the plates 3 times withwash buffer. The adherent cells were broken by addition of 1% TritonX-100 (Nacalai Tesque, 355-01). Released CFSC was quantifiedfluorescence measurement in a fluorometer (Wallac, ARVO 1420 multilabelcounter).

The adhesion of Ramos cells to VCAM-1 was analyzed by percent bindingcalculated by the formula:

100×(FTS−FBG)/(FTB−FBG)=% binding, where FTB is the total fluorescentintensity from VCAM-1 coated wells without test compound; FBG is thefluorescent intensity from wells with anti-CD49d monoclonal antibody andFTS is the fluorescent intensity from wells containing the test compoundof this invention.

In Vitro Activity:

In the Jurkat-VCAM-1 assay (indicated as Jurkat-VCAM-1) and theRamos-VCAM-1 (indicated as Ramos-VCAM-1) the observed IC₅₀ value rangesare indicated Table 4.D>10μM≧C>2 μM≧B>0.5 μM≧A TABLE 4 Example No. IC₅₀ 37 A 38 A 39 A 40 A 41A 42 A 43 A 44 A 45 A 46 A 47 A 49 A 50 A 51 D 52 D 53 B  ^( 53a) A 54 A56 A 57 A 58 A 59 A 60 A 61 A 62 A 63 A 64 A 65 A 66 A 67 A 68 A 69 A 70A 71 A 72 A 73 A 74 A 75 A 76 A 77 A 78 B 79 C 80 D 81 A 82 A 83 A 84 B85 A 86 A 87 A 88 A 89 A 90 A 91 B 92 B

1. A compound of the general formula (I),

wherein R¹ represents hydrogen, C₁-C₄-alkyl, trifluormethyl,trifluormethoxy, phenyl, —OR¹⁻², —SR¹⁻², NR¹⁻³R¹⁻⁴, —C(O)R¹⁻², S(O)R¹⁻²,—SO₂R¹⁻², —CO₂R¹⁻², —OC(O)R¹⁻², —C(O)NR¹⁻³R¹⁻⁴, —NR¹⁻²C(O)R¹⁻²,—SO₂NR¹⁻³R¹⁻⁴, —NR¹⁻² SO₂R¹⁻², —NR¹⁻²C(O)NR¹⁻³R¹⁻⁴, —NR¹⁻²C(O)OR¹⁻⁴,—OC(O)NR¹⁻³R¹⁻⁴, halogen, cyano, nitro or amino, wherein R¹⁻² representshydrogen or C₁-C₄-alkyl, wherein R¹⁻³ represents hydrogen orC₁-C₄-alkyl, R¹⁻⁴ represents hydrogen, C₁-C₄-alkyl, C₃-C₆-cycloalkyl,C₆- or C₁₀-aryl, heteroaryl or a heterocycle, wherein R¹⁻⁴ canoptionally be substituted by 1 to 2 substituents selected from the groupconsisting of C₁-C₄-alkyl, phenyl, C₃-C₇-cycloalkyl, C₁-C₄-alkyloxy,halogen, nitro, and cyano, R² represents hydrogen or halogen, or R¹ andR² together form a 4-7-membered ring, which includes the carbon atoms towhich R¹ and R² are bonded and which contains up to 2 additionalheteroatoms selected from the group consisting of oxygen, nitrogen ofand sulfur and which contains up to 2 double bonds, wherein the ringformed by R¹ and R² can optionally be substituted by —NH—C₆— orC₁₀-aryl, —NH-heterocyclyl or —NH-heteroaryl, wherein C₆- or C₁₀-arylcan optionally be substituted by 1 to 2 substituents halogen,C₁-C₄-alkyl or C₁-C₄-alkoxy, R³ represents hydrogen, C₁-C₁₀-alkyl,C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl, —(CH₂)_(m)—C₆— or C₁₀-aryl,—(CH₂)_(m)—C₃-C₇-cycloalkyl, —(CH₂)_(m)-heterocyclyl or—(CH₂)_(m)-heteroaryl, wherein m represents an integer of zero to six,wherein R³ can optionally be substituted by 1 to 3 radicals R³⁻¹,wherein R³⁻¹ represents trifluormethyl, trifluormethoxy, —OR³⁻²,—NR³⁻³R³⁻⁴, —C(O)R³⁻², halogen, cyano, nitro, oxo, C₆- or C₁₀-aryl,heterocyclyl, or heteroaryl, wherein R³⁻² represents hydrogen,C₁-C₄-alkyl, C₃-C₆-cycloalkyl, or C₆- or C₁₀-aryl, and wherein R³⁻³ andR³⁻⁴ are identical or different and represent hydrogen or C₁-C₄-alkyl,R⁴ represents hydrogen, halogen, C₁-C₄-alkyl, C₁-C₄-alkoxy, cyano, aminoor nitro, R⁵ represents hydrogen, C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl,C₂-C₁₀-alkynyl, —(CH₂)_(n)—C₆— or C₁₀-aryl, —(CH₂)_(n)—C₃-C₇-cycloalkyl,—(CH₂)_(n)-heterocyclyl, or —(CH₂)_(n)-heteroaryl, wherein n representsan integer of zero to six, wherein R⁵ can optionally be substituted by 1to 3 radicals R⁵⁻¹, wherein R⁵⁻¹ represents C₁-C₄ alkyl, trifluormethyl,trifluormethoxy, —OR⁵⁻², —NR⁵⁻³R⁵⁻⁴, —C(O)R⁵⁻², halogen, cyano, nitro,oxo, C₆- or C₁₀-aryl, heterocyclyl, or heteroaryl, wherein R⁵⁻²represents hydrogen, C₁-C₄-alkyl, C₃-C₆-cycloalkyl, C₆- or C₁₀-aryl orhalogenated C₆- or C₁₀-aryl, and wherein R⁵⁻³ and R⁵⁻⁴ are identical ordifferent and represent hydrogen or C₁-C₄-alkyl, or R³ and R⁵ togetherform a 4-7-membered heterocyclic ring, which includes the nitrogen atomto which R⁵ is bonded and the carbon atom to which R³ is bonded andwhich contains up to 2 additional heteroatoms selected from the groupoxygen, nitrogen and sulfur and which contains up to 2 double bonds, R⁶represents hydrogen, C₁-C₄ alkyl, —OR⁶⁻¹, —NR⁶⁻²R⁶⁻³, —C(O)R⁶⁻¹,C₆-aryl, heterocyclyl, heteroaryl, halogen, cyano, nitro, hydroxy,amino, trifluoromethyl, or trifluoromethoxy, wherein R⁶⁻¹ representshydrogen, C₁-C₄-alkyl, C₃-C₆-cycloalkyl or C₆-aryl, wherein R⁶⁻² andR⁶⁻³ are identical or different and represent hydrogen, C₁-C₄-alkyl,C₃-C₆-cycloalkyl or C₆-aryl, and wherein R⁶, R⁶⁻¹, R⁶⁻² and R⁶⁻³ canoptionally be substituted by 1 to 2 radicals R⁶⁻⁴, wherein R⁶⁻⁴represents trifluoromethyl, trifluoromethoxy, halogen, cyano, nitro,hydroxy, amino and or oxo R⁷ represents hydrogen or C₁-C₄ alkyl, or R⁷and R³ together with the carbon atoms to which they are bonded form acycloalkyl ring, X represents oxygen or two hydrogen atoms, or apharmaceutically acceptable salt thereof.
 2. The compound according toclaim 1, wherein R¹ represents —NR¹⁻²C(O)NR¹⁻³R¹⁻⁴, wherein R¹⁻²represents hydrogen, wherein R¹⁻³ represents hydrogen, wherein R¹⁻⁴represents C₆- or C₁₀-aryl or pyridyl, wherein R¹⁻⁴ can optionally besubstituted by 1 to 2 substituents C₁-C₄-alkyl, C₁-C₄-alkoxy or halogen,R represents hydrogen, halogen, C₁-C₄-alkyl or C₁-C₄-alkoxy, or R¹ andR² together form a 4-6-membered heterocyclic or heteroaromatic ring,which includes the carbon atoms to which R¹ and R² are bonded and whichcontains 1 or 2 additional heteroatoms selected from the groupconsisting of oxygen and nitrogen and which contains 1 or 2 doublebonds, wherein the ring formed by R¹ and R² can optionally besubstituted by —NH—C₆— or C₁₀-aryl, wherein C₆- or C₁₀-aryl canoptionally be substituted by 1 to 2 substituents halogen, C₁-C₄-alkyl orC₁-C₄-alkoxy, R³ represents hydrogen, C₁-C₁₀-alkyl, —(CH₂)_(m)—C₆— orC₁₀-aryl, —(CH₂)_(m)—C₃-C₇-cycloalkyl, —(CH₂)_(m)-heterocyclyl, or—(CH₂)_(m)-heteroaryl, wherein m represents an integer of one to four,wherein R³ can optionally be substituted by 1 to 2 radicals R³⁻¹,wherein R³⁻¹ represents —OR³⁻², —NR³⁻³R³⁻⁴, —C(O)R³⁻², halogen, cyano,nitro, oxo, C₆- or C₁₀-aryl, heterocyclyl, or heteroaryl, wherein R³⁻²represents hydrogen or C₁-C₄-alkyl, and wherein R³⁻³ and R³⁻⁴ areidentical or different and represent hydrogen or C₁-C₄-alkyl, R⁴represents hydrogen, halogen, C₁-C₄-alkyl or C₁-C₄-alkoxy, R⁵ representshydrogen, C₁-C₁₀-alkyl, —(CH₂)_(n)—C₆— or C₁₀-aryl,—(CH₂)_(n)—C₃-C₇-cycloalkyl, —(CH₂)_(n)-heterocyclyl, or—(CH₂)_(n)-heteroaryl, wherein n represents an integer of one to three,wherein R⁵ can optionally be substituted by 1 to 2 radicals R⁵⁻¹,wherein R⁵⁻¹ represents C₁-C₄-alkyl, —OR⁵⁻², —NR⁵⁻³R⁵⁻⁴, —C(O)R⁵⁻²,halogen, cyano, nitro, oxo, C₆- or C₁₀-aryl, heterocyclyl, orheteroaryl, wherein R⁵⁻² represents hydrogen or C₁-C₄-alkyl, and whereinR⁵⁻³ and R⁵⁻⁴ are identical or different and represent hydrogen orC₁-C₄-alkyl, R⁶ represents hydrogen, R⁷ represents hydrogen or C₁-C₄alkyl, or R⁷ and R³ together with the carbon atoms to which they arebonded form a cycloalkyl ring, X represents oxygen or two hydrogenatoms, R⁷ represents hydrogen, X represents oxygen, or apharmaceutically acceptable salt thereof.
 3. The compound according toclaim 1, wherein R¹ represents —NR¹⁻² C(O)NR¹⁻³R¹⁻⁴, wherein R¹⁻²represents hydrogen, wherein R¹⁻³ represents hydrogen, wherein R¹⁻⁴represents C₆-aryl, wherein R¹⁻⁴ is substituted by 1 to 2 substituentsC₁-C₄-alkyl, R² represents hydrogen, or R¹ and R² together form a5-membered heterocyclic or heteroaromatic ring, which includes thecarbon atoms to which R¹ and R² are bonded and which contains 1 or 2additional heteroatoms selected from the group consisting of oxygen andnitrogen and which contains 1 or 2 double bonds, wherein the ring formedby R¹ and R² can optionally be substituted by —NH—C₆ aryl, wherein C₆-or C₁₀-aryl can optionally be substituted by 1 to 2 substituentshalogen, C₁-C₄-alkyl or C₁-C₄-alkoxy, R³ represents hydrogen,C₁-C₁₀-alkyl, —(CH₂)_(m)—C₆-aryl, —(CH₂)_(m)—C₃-C₇-cycloalkyl,—(CH₂)_(m)-heterocyclyl, or —(CH₂)_(m)-heteroaryl, wherein m representsan integer of one or two, wherein R³ can optionally be substituted by 1to 2 radicals R³⁻¹, wherein R³⁻¹ represents —OR³⁻², —NR³⁻³R³⁻⁴,—C(O)R³⁻², halogen, oxo, C₆- or C₁₀-aryl, heterocyclyl, or heteroaryl,wherein R³⁻² represents hydrogen or C₁-C₄-alkyl, and wherein R³⁻³ andR³⁻⁴ are identical or different and represent hydrogen or C₁-C₄-alkyl,R⁴ represents hydrogen, halogen, C₁-C₄-alkyl or C₁-C₄-alkoxy, R⁵represents hydrogen, C₁-C₁₀-alkyl, —(CH₂)_(n)—C₆-aryl,—(CH₂)_(n)—C₃-C₇-cycloalkyl, —(CH₂)_(n)-heterocyclyl, or—(CH₂)_(n)-heteroaryl, wherein n represents an integer of one to three,wherein R⁵ can optionally be substituted by 1 to 2 radicals R⁵⁻¹,wherein R⁵⁻¹ represents C₁-C₄-alkyl, —OR⁵⁻², —NR⁵⁻³R⁵⁻⁴, —C(O)R⁵⁻²,halogen, cyano, nitro, oxo, C₆- or C₁₀-aryl, heterocyclyl, orheteroaryl, wherein R⁵⁻² represents hydrogen or C₁-C₄-alkyl, and whereinR⁵⁻³ and R⁵⁻⁴ are identical or different and represent hydrogen orC₁-C₄-alkyl, R⁶ represents hydrogen, R⁷ represents hydrogen, Xrepresents oxygen, or a pharmaceutically acceptable salt thereof.
 4. Thecompound according to claim 1, wherein R¹ represents a group of theformula


5. The compound according to claim 1, wherein the group of the formula

represents a group of the formula


6. The compound according to claim 1, wherein the group of the formula

represents a group of the formula


7. The compound according to claim 1, wherein R³ represents hydrogen. 8.The compound according to claim 1, wherein the compound is selected fromthe following group:4-[(N²-{[4-({[(2L-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-D-lysyl)-amino]benzoicacid trifluoroacetate,4-[(N-[3-(dimethylamino)propyl]-N-{[4-({[(2-methylphenyl)amino]carbon-yl}amino)phenyl]acetyl}glycyl)amino]benzoicacid,4-[(N-(4-aminobutyl)-N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)-phenyl]acetyl}glycyl)amino]benzoicacid,4-({N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-N-[3-(1-pyrrolidinyl)propyl]glycyl}amino)benzoicacid,4-[(N-[(1-ethyl-2-pyrrolidinyl)methyl]-N-{[4-({[(2-methylphenyl)amino]-carbonyl}amino)phenyl]acetyl}glycyl)amino]benzoicacid,4-({N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-N-[3-(4-phenyl-1-piperazinyl)propyl]glycyl}amino)benzoicacid,4-{[N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-N-(tetrahydro-2-furanylmethyl)glycyl]amino}benzoicacid,4-{[N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-N-(4-piperidinylmethyl)glycyl]amino}benzoicacid,4-[(N-(3-amino-2,2-dimethylpropyl)-N-{[4-({[(2-methylphenyl)amino]-carbonyl}amino)phenyl]acetyl}glycyl)amino]benzoicacid,4-({N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-N-[2-(1-pyrrolidinyl)ethyl]glycyl}amino)benzoicacid,4-[(N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-N-propylglycyl)amino]benzoicacid,4-({N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-N-[3-(2-oxo-1-pyrrolidinyl)propyl]glycyl}amino)benzoicacid,4-[(N-(2-methoxyethyl)-N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)-phenyl]acetyl}glycyl)amino]benzoicacid,4-({N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-N-[3-(4-morpholinyl)propyl]glycyl}amino)benzoicacid, 4-{[N{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-N-(3-pyridinylmethyl)glycyl]amino}benzoicacid,4-{[N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-N-(2-pyridinylmethyl)glycyl]amino}benzoicacid,4-{[N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-N-(4-yridinylmethyl)glycyl]amino}benzoicacid,4-[(N-[2-(1H-imidazol-4-yl)ethyl]-N-{[4-({[(2-methylphenyl)amino]carbon-yl}amino)phenyl]acetyl}glycyl)amino]benzoicacid,4-({N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-N-[2-(2-pyridinyl)ethyl]glycyl}amino)benzoicacid, 4-({N-[(2-anilino-1,3-benzoxazol-6-yl)acetyl]glycyl}amino)benzoicacid,4-{[N-[(2-anilino-1,3-benzoxazol-6-yl)acetyl]-N-(2-phenylethyl)glycyl]-amino}benzoicacid,4-({N-[(2-anilino-1,3-benzoxazol-6-yl)acetyl]-N-[2-(2-pyridinyl)ethyl]-glycyl}amino)benzoicacid,4-({N-[(2-anilino-1,3-benzoxazol-6-yl)acetyl]-N-[2-(3,5-dimethoxyphenyl)-ethyl]glycyl}amino)benzoicacid,4-{[N-({2-[(2-methylphenyl)amino]-1,3-benzoxazol-6-yl}acetyl)glycyl]amino}-benzoicacid,4-{[N-({2-[(2-methylphenyl)amino]-1,3-benzoxazol-6-yl}acetyl)-N-(2-phenylethyl)glycyl]amino}benzoicacid,4-({N-({2-[(2-methylphenyl)amino]-1,3-benzoxazol-6-yl}acetyl)-N-[2-(2-pyridinyl)ethyl]glycyl}amino)benzoicacid,4-[(N-[2-(3-methoxyphenyl)ethyl]-N-{[4-({[(2-methylphenyl)amino]-carbonyl}amino)phenyl]acetyl}glycyl)amino]benzoicacid,4-[(N-benzyl-N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]-acetyl}glycyl)amino]benzoicacid,4-({N-[(2-anilino-1,3-benzoxazol-6-yl)acetyl]-N-[2-(3-methoxyphenyl)-ethyl]glycyl}amino)benzoicacid,4-[(N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-L-phenylalanyl)amino]benzoicacid,4-({N-[(2-anilino-1,3-benzoxazol-6-yl)acetyl]-L-phenylalanyl}amino)benzoicacid,4-[(4-bromo-N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-L-phenylalanyl)amino]benzoicacid,4-[(N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}glycyl)amino]benzoicacid4-{[(2S)-4-amino-2-({[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}amino)butanoyl]amino}benzoicacid4-[(N²-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-L-ornithyl)amino]benzoicacid4-[(N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-L--aspartyl)amino]benzoicacid4-[(N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-L-tryptophyl)amino]benzoicacid4-{[N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-3-(4-pyridinyl)-L-alanyl]amino}benzoicacid4-{[N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-3-(3-pyridinyl)-L-alanyl]amino}benzoicacid4-{[N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-3-(1,3-thiazol-4-yl)-L-alanyl]amino}benzoicacid4-[(N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-L-histidyl)amino]benzoicacid4-{[(1-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}-2-piperazinyl)carbonyl]amino}benzoicacid4-[3-({[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}amino)-1-piperidinyl]benzoicacid4-[3-({[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}amino)-1-pyrrolidinyl]benzoicacid4-[isobutyl(N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}glycyl)amino]benzoicacid4-[isobutyl(N-(3-methoxypropyl)-N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}glycyl)amino]benzoicacid and4-[(N-(3-methoxypropyl)-N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}glycyl)(methyl)amino]benzoicacid.
 9. (Cancelled)
 10. A method for the treatment or the prevention ofa condition mediated by integrins comprising administering an effectiveamount of a compound of claim
 1. 11. The method of claim 10 wherein saidcondition mediated by integrins is selected from the group consisting ofatherosclerosis, asthma, chronic obstructive pulmonary disease (COPD),allergies, diabetes, inflammatory bowel disease, multiple sclerosis,myocardial ischemia, rheumatoid arthritis, transplant rejection andother inflammatory, autoimmune and immune disorders.
 12. Apharmaceutical composition, comprising a compound according to claim 1and a pharmaceutically acceptable carrier.
 13. (Cancelled)